1. Introduction

2. Drugs used in ADs

3. Genetic variations that can

modify the metabolism of

drugs used in the treatment

of ADs

4. Conclusion

5. Expert opinion

Review

Metabolic considerations of drugsin the treatment of allergicdiseasesElena Garcıa-Martın†, Gabriela Canto & Jose AG Ag�undez†University of Extremadura, Department of Biochemistry & Molecular Biology, Caceres, Spain

Introduction: The clinical management of allergic diseases involves a number

of drugs, most of which are extensively metabolized. This review aims to ana-

lyze the metabolism and the clinical implications of altered metabolism for

these drugs.

Areas covered: The authors present an overview of current knowledge of the

metabolism of: antihistamine drugs, glucocorticoids, inhaled b-2 broncho-

dilators, anticholinergics and other drugs used in allergic diseases, such as

cromoglycate, omalizumab, montelukast and epinephrine. Polymorphic

drug metabolism is relevant for chlorpheniramine, loratadine and montelu-

kast. Inhibition of drug metabolism is relevant for loratadine, methylprednis-

olone, fluticasone, mometasone, triamcinolone or prednisolone. Polymorphic

pre-systemic metabolism may be relevant to budesonide, fluticasone, beclo-

methasone, mometasone or salmeterol. The authors also discuss the current

information on gene variations according to the 1,000 genomes catalog and

other databases. Finally, the authors review the clinical implications of these

variations with a particular regard to drugs used in the management of

allergic diseases.

Expert opinion: Most drugs used in allergic diseases are extensively meta-

bolized. Drug interaction or adverse reactions related to altered metabolism

are relevant issues that should be considered in the management of allergic

diseases. However, much additional research is required before defining

pharmacogenomic biomarkers for the management of drugs used in allergic

diseases.

Keywords: b-2 adrenergic agonists, adverse drug reactions, allergy, anticholinergics,

antihistamines, biomarkers, glucocorticoids, interactions, metabolism, pharmacogenomics

Expert Opin. Drug Metab. Toxicol. (2013) 9(11):1437-1452

1. Introduction

The treatment of allergic diseases (ADs) including, among others, asthma, allergicrhinitis, allergic conjunctivitis, urticaria, atopic dermatitis/eczema and anaphylaxis,is based on the management of symptoms rather than treating the underlying causeof the diseases, the reason for this being that, at present, the mechanisms involved inthe etiopathogeny of these diseases are not completely understood.

Therapy of ADs is complex. For instance, asthma is a chronic complex inflamma-tory disease affecting the bronchial tree including both the large and small airways [1].Inhaled glucocorticoids are the most widely used drugs for asthma treatment. Theresponse to treatment for asthma, including all the drugs used, is characterized byinterindividual variability, with up to 40% of patients having no adequate responseto therapy [2]. A similar picture occurs with the current pharmacotherapy strategy ofallergic rhinitis and other ADs.

Drug metabolism is a major determinant of clinical response and of the occur-rence of adverse effects. In this invited review, we analyze the metabolic

10.1517/17425255.2013.823400 © 2013 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 1437All rights reserved: reproduction in whole or in part not permitted

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considerations for drugs used in the treatment of ADs and thecurrent knowledge of metabolic alterations, due to geneticfactors or factors related to enzyme induction or inhibition,which may modify the clinical response to these drugs.The major drug groups used in the management of these dis-

eases include antihistamines, which are used orally or as nasal orophthalmic solutions. Antihistamines are medications of choicefor allergic rhinitis, allergic conjunctivitis and chronic urticaria [3].Another important group of drugs is glucocorticoids, which areused orally, as inhalants, as nasal or eye drops or injected. Otheradministered drugs and inhalants include b-2 bronchodilators oranticholinergics. We will discuss the metabolic implications ofthese drugs and of other drugs which do not belong to the cate-gories mentioned, such as cromoglycate, omalizumab, montelu-kast and epinephrine, with emphasis on polymorphic drugmetabolism and enzyme induction or inhibition properties ofthese drugs which may modify clinical response.

2. Drugs used in ADs

2.1 AntihistaminesAntihistamine drugs used in ADs are histamine H1 receptor(HRH1) inverse agonists [3]. Histamine interacts with fourmetabotropic receptor types designed as HRH1 to HRH4which are polymorphic [4]. HRH1 is involved in hypersensi-tivity reactions, smooth muscle contraction and vascular per-meability. HRH2 modulates gastric acid secretion, and bothHRH1 and HRH2 are involved in numerous processes ofimmune response [5]. HRH3 acts as an autoreceptor in thenervous system by inhibiting histamine synthesis and itsrelease. HRH3 also acts as a heteroreceptor, modulating therelease of other neurotransmitters, including acetylcholine,

dopamine and noradrenaline. HRH4 has a higher affinityfor histamine than HRH1 and appears to be more selectivelyexpressed, being found mainly on hematopoietic cells.HRH4 is involved in chemotaxis and in the release of inflam-matory mediators by eosinophils, mast cells, monocytes, den-dritic cells and T cells, and it is involved in immune controlmechanisms in different organs and tissues, such as the spleen,the thymus and leukocytes [5].

HRH1 inverse agonists bind HRH1 and stabilize theinactive conformation of the receptor. These drugs are func-tionally classified into two groups: first-generation H1-anti-histamines readily cross the blood--brain barrier and bind toacetylcholine and serotonin receptors and calcium channels [6].Second-generation H1-antihistamines do not readily cross theblood--brain barrier [6] and hence cause fewer effects in thecentral nervous system (CNS).

Indications for H1-antihistamines include perennial andseasonal allergic rhinitis, vasomotor rhinitis, allergic conjunc-tivitis due to inhalant allergens and foods, allergic skinmanifestations of urticaria and angioedema and pruritus.

2.1.1 Cetirizine, levocetirizineCetirizine is a potent second-generation HRH1 inhibitor cur-rently administered as a racemic mixture of (R)-levocetirizineand (S)-dextrocetirizine. Unlike many traditional antihist-amines, it does not cause drowsiness or anticholinergic sideeffects. However, cetirizine is not completely devoid of CNSeffects. Tashiro et al. [7] found that after a double therapeuticdose of 20 mg, cetirizine occupied 20 to 50% of the H1 recep-tors in the brain. In comparison, 2 mg dexchlorpheniramineoccupies 77% of the H1 receptors and has been shown toinduce clear behavioral effects and sedation [8]. The 50%receptor occupancy in the CNS by cetirizine may be sufficientto induce behavioral effects. Plasma protein binding is veryhigh -- about 93%. Cetirizine has a mean elimination half-life of 7.4 h [9]. Cetirizine is poorly metabolized, with 80%of the dose excreted in urine and feces as unchanged drug.One minor metabolite results from oxidative O-dealkylationof cetirizine [9]. Other metabolic pathways are glucurocon-jugation, taurine conjugation and glutathione conjugationwith formation of the mercapturic acids. It has neither induc-ing nor inhibiting effects on major drug metabolizing enzymesand therefore can be safely administered with other drugs.

2.1.2 ChlorpheniramineChlorpheniramine is a first-generation HRH1 inverse agonistof the alkylamine class. It is well absorbed in the gastrointes-tinal tract and shows a half-life of about 20 -- 30 h. After mul-tiple doses, it accumulates in the liver and inhibits theCYP2D6 [10,11] enzyme. Chlorpheniramine is primarilymetabolized in the liver via cytochrome P450 (CYP450)enzymes, CYP2D6, CYP3A4, CYP3A5 and CYP3A7 [12,13].It has been shown that chlorpheniramine pharmacokineticsis influenced by the CYP2D6 polymorphism, individualswith poor metabolizer genotypes showing increased exposure

Article highlights.

. Most drugs used in ADs are extensively metabolizedin humans.

. Polymorphic drug metabolism is a relevant factor in thepharmacokinetics or in the clinical response to some ofthese drugs, for instance, chlorpheniramineand loratadine.

. Presystemic metabolism of inhaled drugs which areCYP3A4/5 substrates, such as budesonide, fluticasone,beclomethasone, mometasone and salmeterol, is likelyto be influenced by a common CYP3A5 diplotype whichaffect about 10% of individuals.

. Inhibition of drug-metabolizing enzymes is a relevantfactor in the pharmacokinetics or in the clinical responseto some of these drugs, for instance, loratadine,methylprednisolone, fluticasone, mometasone,triamcinolone or prednisolone.

. Because many drugs used in ADs are metabolized bythe same enzymes and can modify the metabolism ofother drugs used in ADs, drug interaction related toaltered metabolism is a relevant issue that should beconsidered in the management of ADs.

This box summarizes key points contained in the article.

E. Garcıa-Martın et al.

1438 Expert Opin. Drug Metab. Toxicol. (2013) 9(11)

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to the drug [14] and increased risk of developing adverseeffects [15].

2.1.3 EbastineEbastine is a long-acting, second-generation, selective HRH1inverse agonist. After oral administration, ebastine undergoesextensive first-pass metabolism. Ebastine is rapidly oxidizedto carebastine, which is the major metabolite and is thoughtto be responsible for the pharmacological effects [16]. Carebas-tine has a mean elimination half-life of 15 to 19 h. The inac-tive metabolites hydroxyebastine and desalkylebastine arealso formed [17]. The major enzymes involved in ebastinemetabolism are CYP2J2, CYP3A4 and CYP4F12 [16]. Thegenes coding for these enzymes are polymorphic and it is con-ceivable that carriers of loss-of-function mutations in thesegenes would show altered response to ebastine. However, nostudies assessing the effect of polymorphisms in the genescoding for ebastine metabolism and the occurrence of adverseeffects with this drug have been carried out so far.

2.1.4 HydroxyzineHydroxyzine is a first-generation HRH1 inhibitor that isused in the treatment of dermatitis, chronic urticaria andhistamine-mediated pruritus. Unlike its major metabolitecetirizine, which is also used as an HRH1 antagonist (seeabove), hydroxyzine does cause drowsiness. Hydroxyzine isalso useful as an antiemetic, for the management of anxietyand tension, and as a sedative. The sedative properties ofhydroxyzine occur at the subcortical level of the CNS.Hydroxyzine has a half-life of about 20 -- 25 h and it is metab-olized in liver. The involvement of enzymes responsible forhydroxyzine metabolism remains to be fully understood [12,13].Hydroxyzine is an inhibitor of CYP2D6 and hence, the con-comitant use of hydroxyzine with other CYP2D6 substratesmay lead to altered biodisposition of these substrates andthereby to adverse reactions.

2.1.5 KetotifenKetotifen inhibits HRH1 response and is a mast cell stabilizer.Ketotifen inhibits the release of mediators from mast cellsinvolved in hypersensitivity reactions, decreases chemotaxisand activates eosinophils. When taken orally, ketotifen is use-ful in asthma. When administered as an ophthalmic solution,it is used to treat allergic conjunctivitis [12,13].

Biotransformation of ketotifen is primarily hepatic. Themain metabolite found in both plasma and urine is the inac-tive ketotifen-N-glucuronide. Other metabolites detectablein urine are nor-ketotifen, the N-demethylated metabolite,and the 10-a-hydroxyl derivative [18]. Since the use of ketoti-fen in ADs is limited to the ophthalmic solution, ketotifenmetabolism has no clinical relevance in this context.

2.1.6 LevocabastineLevocabastine is a potent selective HRH1 whose main indi-cations are as ophthalmic solution for seasonal allergic

conjunctivitis and as a nasal spray for allergic rhinitis [19]. Attherapeutic doses, levocabastine appears to be devoid of signi-ficant systemic activity and only low plasma levels of the drugare attained following topical administration [19]. Moreover,levocabastine is poorly metabolized and, therefore, no meta-bolic implications apply for the management of ADs withthis drug.

2.1.7 Loratadine, desloratadineLoratadine is a second-generation HRH1 inhibitor derivativeof azatadine. Loratadine appears to suppress the release of his-tamine and leukotrienes from mast cells, and the release ofleukotrienes from human lung fragments, although the clini-cal importance of these effects is unknown. Loratadine under-goes extensive first-pass metabolism and shows a half-lifeof about 8 h [13]. Several enzymes contribute to loratadinemetabolism. These include CYP3A4, CYP2D6, CYP1A1,CYP2C19 and, to a lesser extent, CYP1A2, CYP2B6,CYP2C8, CYP2C9 and CYP3A5 [20,21]. It has been shownthat loratadine pharmacokinetics is altered in carriers of defec-tive CYP2D6 alleles [22]. In addition, CYP3A4 inhibitionresults in increased bioavailability of loratadine in animalmodels [23].

Desloratadine is the main metabolite of loratadine. It has aselective and peripheral H1-inhibitor action and a long-lasting effect and does not cause drowsiness. Desloratadinehas a mean half-life of 27 h [13] and is extensively metabolizedto 3-hydroxydesloratadine, an active metabolite which is sub-sequently glucuronidated. Approximately 87% of deslorata-dine administrated was equally recovered in urine andfeces [12,13]. The enzyme(s) responsible for the formation of3-hydroxydesloratadine have not been identified, but it hasbeen shown that inhibition of the CYP2D6 enzyme doesnot result in desloratadine pharmacokinetic alterations [24].Unlike loratadine, no studies on the effect of CYP2D6 poly-morphisms in desloratadine pharmacokinetics have beenperformed so far.

2.1.8 OlopatadineOlopatadine is a second-generation HRH1 inhibitor whichis used in treating ocular itching associated with allergic con-junctivitis. After oral administration, olopatadine is meta-bolized by N-demethylation and N-oxidation in humansmainly by CYP3A4 and FMO enzymes [25]. Ophthalmic useof olopatadine does not usually produce a measurable plasmaconcentration [26] and therefore when it is used in the form ofeye drops no metabolic implications apply to this drug.

2.1.9 RupatadineRupatadine is a second-generation HRH1 inhibitor thatinhibits platelet-activating factor receptors. Rupatadine has amean half-life of 6 h [13]. The primary metabolic pathway ofrupatadine catalyzed by CYP3A4 leads to the formation ofdesloratadine [27]. Although it has been claimed that rupata-dine is not subject to polymorphic metabolism [28], it should

Metabolic considerations of drugs in the treatment of AD

Expert Opin. Drug Metab. Toxicol. (2013) 9(11) 1439

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be taken into consideration that metabolites from rupatadine,including desloratadine and the hydroxylated metaboliteshave antihistamine activity and that desloratadine (see above)or other rupatadine metabolites may be polymorphicallymetabolized [27].

2.2 GlucocorticoidsGlucocorticoids are known to have different actions depend-ing on cell type [29]. Glucocorticoid receptor activation regu-lates gene transcription, switches on anti-inflammatory genesand switches off multiple inflammatory genes. Additionallyglucocorticoids also modulate post-transcriptional mechanismof the inflammation.Glucocorticoids are the most effective anti-inflammatory

drugs available for the treatment of asthma. Most patientsare controlled with inhaled glucocorticoids despite the factthat some are resistant to treatment and that the mechanismsunderlying such resistance are still unknown [30].When glucocorticoids are topically administered in pro-

longed treatment on large body areas, significant drug absorp-tion may occur. Sporadic case reports suggest that ocularsteroids also carry a risk of systemic complications. The riskis highest with high potency corticosteroids. In addition,because infants and young children have a high ratio ofbody surface area compared to their weight, they are especiallysusceptible to corticosteroid absorption. The extent of absorp-tion is greater for inflamed skin and other skin conditionssuch as eczema and psoriasis.

2.2.1 BeclometasoneBeclometasone is a synthetic halogenated glucocorticoid. Itis used as an inhalant or is used topically as an anti-inflamma-tory agent for the treatment of allergic or nonallergic rhinitisand recurrent nasal polyps and in aerosol form for thetreatment of asthma. It is administrated as beclometasonedipropionate, a prodrug of beclometasone which is rapidlymetabolized via esterase enzymes that are found in most tis-sues. Peak plasma concentrations are usually achieved after30 min and half-life is about 3 h. Beclometasone is metabo-lized by CYP3A4 and CYP3A5 [31] and the parent drug andits metabolites are mainly excreted in the feces. Less than10% of the drug or its metabolites are excreted in the urine.

2.2.2 BudesonideBudesonide is a synthetic corticosteroid used in the treatmentof asthma, various skin disorders and allergic rhinitis. Budeso-nide has a high topical glucocorticosteroid activity and, whenadministered orally, it shows a substantial first-pass metabo-lism (80 -- 90%). It is used as an inhalant for most ADs(Table 1) and is used orally for Crohn’s disease. Budesonideshows a half-life between 2 and 4 h. In vitro experiments onhuman liver microsomes suggest that budesonide is rapidlyand extensively biotransformed, mainly by CYP3A4, to itstwo major metabolites, 6b-hydroxy budesonide and 16a-hydroxy prednisolone, both with negligible glucocorticoid

activity. In the lungs, CYP3A5 efficiently metabolizes budeso-nide [32]. No pharmacogenetic recommendations on the use ofbudesonide based on CYP3A4/5 genotypes have been formu-lated and further studies are required to evaluate budesonidebioavailability, when administered as inhalant, in individualsexpressing high CYP3A5 activity.

2.2.3 CiclesonideThis is used for the treatment of nasal symptoms associatedwith seasonal and perennial allergic rhinitis in adults and ado-lescents 12 years of age and older and as an inhalant for themanagement of asthma [33]. Following intranasal application,ciclesonide is enzymatically hydrolyzed to the pharmacologi-cally active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide), which shows a half-life of 6 -- 7 h and undergoesmetabolism in the liver to additional metabolites mainlyby CYP3A4 and CYP2D6. Ciclesonide and des-ciclesonidehave negligible oral bioavailability due to low gastrointestinalabsorption and high first-pass metabolism. The intranasaladministration of ciclesonide at recommended doses resultsin negligible serum concentrations of ciclesonide, and there-fore the metabolic implications for intranasal use of thisdrug are of low relevance. In contrast, ciclesonide systemiceffects when administered as an inhalant require furtherstudies to be fully understood [34].

2.2.4 DeflazacortDeflazacort is an oxazoline derivative of prednisolone withanti-inflammatory and immunosuppressive properties. Defla-zacort is a prodrug which is activated by plasma esterases tothe biologically active metabolite 21-deacetyl-deflazacort [35].Deflazacort is well absorbed and peak plasma concentrationsof the active metabolite occur within 1 to 2 h. Half-life isabout 1 to 2 h [36], and the drug is eliminated in urine andfeces. No major clinical implications of altered deflazacortmetabolism have been reported, probably due to the rapidelimination of the active deflazacort metabolite [37].

2.2.5 DexamethasoneDexamethasone and its derivatives, dexamethasone sodiumphosphate and dexamethasone acetate, are synthetic gluco-corticoids. These drugs are used because of their anti-inflammatory and immunosuppressive properties and theirability to cross the brain barrier. Dexamethasone is wellabsorbed and has a relatively long half-life of about 36 to54 h. Dexamethasone is mainly metabolized by 6-hydroxyl-ation to 6-a and 6-b hydroxydexamethasone, and minor met-abolic pathways include side chain cleavage or oxidation ofboth metabolites [38]. Indirect evidence points to CYP3A4 asa major enzyme involved in dexamethasone metabolism [38].Because of the lack of CYP3A4 genotype/phenotype associa-tion, no genetic polymorphisms capable of influencingdexamethasone metabolism have been described. However,dexamethasone should be cautiously used when co-adminis-tered with CYP3A4 substrates, inducers or inhibitors because

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dexamethasone metabolism may be affected by these drugs andbecause dexamethasone is a potent CYP3A4 inducer [39,40].

2.2.6 Fluticasone propionateFluticasone propionate, a synthetic corticosteroid, is used orallyor as an inhalant for the treatment of asthma and is used topi-cally to relieve inflammatory and pruritic symptoms of derma-toses and psoriasis. Intranasal use of fluticasone propionate isuseful for managing symptoms of allergic and non-allergic rhinitis. Half-life is about 10 h, and the drug is metab-olized in the liver by CYP3A4 to the inactive 17-(b)-carboxylicacid metabolite, the only known metabolite detected inman [41]. Adrenal insufficiency has been described in patientstreated with fluticasone in combination with CYP3A4 inhibi-tors such as fluconazole [42] or ritonavir [43], thus suggestingthat the concomitant use of fluticasone and CYP3A4 inhibitorsmay increase the risk of severe adverse effects. The CYP3A4inhibitor ketoconazole increases systemic exposure to flutica-sone [44], and the association of the CYP3A4*22 gene variant,leading to decreased CYP3A4 activity, has been reported,with a better control of asthma in patients treated with flutica-sone [45]. In spite of this evidence, no pharmacogenetic recom-mendations on the use of fluticasone based on CYP3A4 activityor genotype have been formulated so far.

2.2.7 HydrocortisoneTopical hydrocortisone is used because of its anti-inflamma-tory and immunosuppressive activity to treat inflammationdue to corticosteroid-responsive dermatoses. Hydrocortisoneis used as an injection in the treatment of inflammation, col-lagen diseases, asthma, adrenocortical deficiency, shock andsome neoplastic conditions. Even when hydrocortisone isused topically, it should be borne in mind that topical cortico-steroids can be absorbed from normal intact skin and thenmetabolized. Half-life is 6 to 8 h and it is metabolized inthe liver via CYP3A4 to the 6-b hydroxy metabolite. Theuse of the metabolic ratio 6-b hydroxycortisol:cortisol hasbeen proposed as an index of CYP3A4 metabolic capacityin vivo and, in particular, to test the effect of CYP3A4inducers [46] or inhibitors [47].

2.2.8 MethylprednisoloneThis is a prednisolone derivative with similar anti-inflam-matory action. The pharmacokinetics is similar to that of pred-nisolone and shows a half-life of 1 to 3 h [13] and is metabolizedin the liver. Methylprednisolone is a CYP3A4 substrate, andwhen CYP3A4 is inhibited, plasma concentrations and effectsof oral methylprednisolone are considerably increased [48].Common CYP3A4 variations do not show a strong associationwith CYP3A4 phenotype [49,50]. However, the concomitantadministration of CYP3A4 substrates, inducers or inhibitormay modify clinical response to this drug. For an updated tableof CYP3A4 inhibitors, see the website [51].

2.2.9 MometasoneMometasone is a medium-potency synthetic corticosteroid.It is administered as an inhalant for the maintenance ofasthma [52] and a nasal spray for nasal symptoms of allergicrhinitis. When used intranasally, the drug is virtually unde-tectable in plasma [53]. Mometasone has a half-life of about6 h [13] and is converted into several metabolites, someof which are active [54]. Indirect evidence suggests thatCYP3A4 may be a major enzyme involved in mometasonemetabolism, and adverse reactions related to the use of mome-tasone and CYP3A4 inhibitors have been reported [55], thussuggesting that mometasone should be used with cautionwhen co-administered with CYP3A4 substrates or inhibitors,because of the risk of adverse reactions. Because CYP3A5 isthe major form of CYP3A expressed in the human lung,and because CYP3A4 and CYP3A5 share substrate speci-ficities, it is conceivable that in CYP3A5 expressers, a substan-tial part of inhaled mometasone may be presystemicallyinactivated. This point requires further investigation.

2.2.10 Prednisone and prednisolonePrednisone is a synthetic anti-inflammatory glucocorticoidderived from cortisone. It is biologically inert and it is con-verted in the liver to the active metabolite prednisolone [56]

by 11-b-hydroxysteroid dehydrogenase activity. Both pred-nisone and prednisolone are readily absorbed from the gas-trointestinal tract, and in plasma are extensively bound toplasma proteins. Prednisone is rapidly absorbed after oraladministration and shows a half-life of about 1 h, whereasthe half-life of prednisolone is about 2 -- 3 h. The metabo-lism of prednisolone is diminished in patients treated withcyclosporine [57].

2.2.11 TriamcinoloneTriamcinolone and its derivatives are synthetic glucocorti-coids that are used for the treatment of perennial and seasonalallergic rhinitis. Triamcinolone is a long-acting drug whichcan be administered orally, by injection, by inhalation andas a topical therapy. When orally administered, an extensivepresystemic metabolism is observed [58]. Once absorbed tri-amcinolone shows a half-life of about 2 h [13] and is exten-sively metabolized [58] with CYP3A4 playing a major role intriamcinolone metabolism [32]. Adverse reactions related tothe concomitant use of triamcinolone and CYP3A4 inhibitorshave been reported [59,60].

2.3 b-2 adrenergic agonistsb-2 adrenergic agonists are currently prescribed for the treat-ment of asthma and chronic obstructive pulmonary disease(COPD) (reviewed in Ref. [61]). Binding of agonists to b-2-receptors in the lungs results in relaxation of bronchial smoothmuscles. The stimulation of b-2-receptors increases cAMPproduction by activating adenylate cyclase. Increased intracellu-lar cAMP increases the activity of cAMP-dependent protein

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kinase A, which inhibits the phosphorylation of myosinand lowers intracellular calcium concentrations. Loweredintracellular calcium concentration leads to a smooth musclerelaxation and bronchodilation. In addition to bronchodilation,b-2-receptors agonists inhibit the release of bronchoconstrictingagents from mast cells, inhibit microvascular leakage andenhance mucociliary clearance. Available b-2-receptor agonistsdiffer in relation to receptor selectivity, onset of relaxation andduration of effect.

2.3.1 FormoterolFormoterol is a long-acting b-2-adrenergic receptor agonistdrug that is currently prescribed for the treatment of asthmaand COPD. Formoterol is also used for the prevention ofexercise-induced bronchospasm, as well as long-term treat-ment of bronchospasm associated with COPD. Inhaled for-moterol fumarate acts locally in the lung as a bronchodilatorwith a rapid onset of action of between 1 and 3 min, and sus-tained, dose-dependent bronchodilatory effects. Formoterol israpidly absorbed following administration by inhalation. Itshows a half-life of about 10 h [13] and is metabolized primar-ily by direct glucuronidation at either the phenolic oraliphatic hydroxyl group. The main metabolite in urine isthe phenol glucuronide of formoterol [62]. Minor pathwaysinvolve O-demethylation followed by glucuronide conjuga-tion at either phenolic hydroxyl groups, sulfate conjugationof formoterol and deformylation followed by sulfate conjuga-tion [63]. Diverse CYP450 isozymes are involved in theO-demethylation of formoterol [12,13].

2.3.2 SalbutamolSalbutamol is a short-acting, selective b-2-adrenergic receptoragonist used in the treatment of acute episodes of broncho-spasm caused by bronchial asthma, chronic bronchitis andother chronic bronchopulmonary disorders such as COPD.It is also used prophylactically for exercise-induced asthma.Salbutamol is formulated as a racemic mixture of the R- and

S-isomers [64]. The R-isomer has 150 times greater affinity forthe b-2-receptor than the S-isomer and the S-isomer has beenassociated with toxicity. Systemic absorption of salbutamol israpid following aerosol administration [65]. Salbutamol ishydrolyzed by esterases in tissues and blood to the activemetabolite colterol. The half-life is 1.6 h [13]. Airway peroxi-dases catalyze nitration of salbutamol which decrease affinityfor receptors and impaired cAMP synthesis [66]. The clinicalrelevance of this remains unknown although an increasedsalbutamol presystemic metabolism in the asthmatic airwayshas been reported, related to increased peroxidase-catalyzednitration, which could diminish the therapeutic effect ofinhaled salbutamol. The drug is also conjugated to salbutamol4¢-O-sulfate by the cytosolic sulfotransferase SULT1A3 [67],and additional metabolites have been reported [68]. Approxi-mately 70% of the inhaled dose is excreted in urine within24 h -- 28% as unchanged drug and 44% as metabolites [69].The identification of SULT1A3 as the major enzyme

catalyzing salbutamol sulfation is recent and, therefore, theeffect of SULT1A3 gene variations in salbutamol metabolismawait further investigation.

2.3.3 SalmeterolSalmeterol is a long-acting b-2-adrenergic receptor agonistdrug that is usually prescribed for severe persistent asthmafollowing previous treatment with a short-acting b agonistsuch as salbutamol. It is concurrently prescribed with a corti-costeroid, such as beclometasone or fluticasone. The half-life is 5 to 6 h [13] and the duration of action lasts ~ 12 h. Lim-ited data are available on the pharmacokinetics of salmeterol.This lack of information is likely due to the fact that systemiclevels of salmeterol are low or undetectable after inhalationat recommended doses [70]. Salmeterol is metabolizedby hydroxylation mediated by CYP3A4, CYP3A5 andCYP3A7. The major metabolite is a-hydroxysalmeterol [71].It is unlikely that altered salmeterol metabolism causes clini-cally relevant effects [70]. As occurs with other inhaled drugsused in the management of ADs that are CYP3A substrates,it is likely that presystemic metabolism in lung tissue mayinfluence the clinical response to salmeterol. The role of themajor CYP3A enzyme expressed in lung, CYP3A5, in salme-terol metabolism and the influence of the CYP3A5 genotypein the response to this drug await further studies.

2.3.4 TerbutalineTerbutaline is a fast-acting b-2-adrenergic agonist that has lit-tle or no effect on a-adrenergic receptors. The drug exerts apreferential effect on b-2-adrenergic receptors but stimulatesother b-adrenergic receptors. Terbutaline is used as a bron-chodilator and tocolytic. This drug has proved to be effectivefor the prevention and reversal of bronchospasm and is gener-ally used as inhalant in the management of ADs. Half-life ofterbutaline is about 5 -- 6 h. When administered as inhalant,the drug effect lasts up to 6 h. About 90% of the drug isexcreted in the urine, about 60% of this being unchangeddrug. Sulfate conjugate could be the major metabolite ofterbutaline, although additional metabolites have beendescribed [68] and urinary excretion is the primary route ofelimination [72]. Although the enzymes responsible for terbu-taline metabolism remain to be identified, because most ofthe drug is excreted unchanged, it is unlikely that adversereactions with terbutaline have a major association toaltered metabolism.

2.4 AnticholinergicsAnticholinergics used for the treatment of obstructive airwaysare synthetic quaternary analogs of atropine including theshort-acting drug ipratropium and the long-acting drug tio-tropium. Muscarinic receptor activation induces bronchocon-striction as well as mucus secretion and may also have animportant regulatory role in b2-receptor agonist function,airway inflammation and airway remodeling (reviewed inRef. [73]). In the airways, acetylcholine is not only a

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neurotransmitter released by parasympathetic nerves but alsoa paracrine or autocrine hormone produced by non-neuronal cells such as epithelial and inflammatory cells.

2.4.1 IpratropiumIpratropium is considered a safe bronchodilator when used asan inhalant. Ipratropium shows a half-life of 2 to 4 h [13] andis partially metabolized to at least eight metabolites formedprimarily by hydrolysis and conjugation. The main metabo-lites are N-isopropylnortropium methobromide, a-phenyla-crylic acid-N-isopropylnortropine-ester methobromide andphenylacetic acid-N-isopropylnortropine-ester methobromide.These metabolites could be inactive [12,13]. Little is knownabout the enzymes involved in ipratropium metabolism andno considerations related to altered ipratropium biodispositionhave been formulated.

2.4.2 TiotropiumTiotropium is a long-acting anticholinergic bronchodilator.Pharmacokinetics studies indicate that little of the inhaleddrug is absorbed [74]. When absorbed, it shows a long half-life of 5 to 6 days [13]. The extent of biotransformation of tio-tropium appears to be small, about 74% of an intravenousdose being excreted unchanged in the urine [75]. Tiotropiumbromide is nonenzymatically cleaved to the alcohol N-methyl-scopine and dithienylglycolic acid, neither of which binds tomuscarinic receptors. In vitro experiments with human livermicrosomes and hepatocytes suggest that a fraction of theadministered dose (25%) is metabolized by CYP450-depend-ent oxidation and glutathione conjugation to Phase IImetabolites [12,13].

2.5 Other drugs2.5.1 CromoglycateCromoglycate (cromoglicic acid) is a chromone complexwhich inhibits the degranulation of mast cells and hence therelease of histamine and other mediators of type I allergicreactions. It is usually administered by inhalation, althoughnasal sprays, eye drops, capsules and solutions are availablein some countries. When inhaled, Cmax occurs in < 30 min.Bioavailability is very low (about 1%) and the drug has ahalf-life of < 90 min [76]. No metabolites have been identifiedin man, and the unchanged drug can be detected in bile andin urine [76].

2.5.2 EpinephrineEpinephrine is a sympathomimetic which is useful in thetreatment of acute hypersensitivity and to relieve broncho-spasm during acute asthmatic attacks. When used for theseindications, epinephrine is administered as intravenous injec-tion. Epinephrine is rapidly and extensively metabolized afteradministration and has a half-life of about 2 min. Because ofthis extremely short half-life, and because many enzymesparticipate in the metabolic inactivation of epinephrine,including monoamine oxidase (MAO) and catechol-O-

methyltransferase (COMT), as well as other enzymes whichconjugate epinephrine metabolites, the study of metabolicimplications for the clinical use of epinephrine is a complexissue. The main enzyme involved in the metabolism of circu-lating epinephrine is the COMT enzyme. Genetic variation inthe COMT gene has been recently reviewed [77] in the light ofthe 1000 genomes data and therefore will not be discussedhere in detail. This gene codes for two enzymes, designatedas S-COMT (soluble COMT) and MB-COMT (mem-brane-bound COMT). Nonsynonymous COMT single-nucleotide polymorphisms (SNPs) are relatively common,but the role of these SNPs in epinephrine metabolism remainsto be elucidated. However, taking into consideration thatmany factors influence epinephrine clearance, it is unlikelythat altered metabolism due to genetic changes in theCOMT gene would lead to adverse reactions related toepinephrine metabolism.

2.5.3 NedocromilNedocromil is a pyranoquinolone derivative that inhibits acti-vation of inflammatory cells. It is usually administered as eyedrops. The half-life of nedocromil is between 3 and 4 h. Thedrug is not metabolized in humans [78] and, when adminis-tered orally, intravenously or by inhalation, most of theabsorbed drug is excreted unchanged in urine. The extent ofabsorption when administered as eye drops is negligible. Sinceboth cromoglycate and nedocromil are eliminated unchangedin humans, no metabolic implications apply to these drugs.

2.5.4 MontelukastMontelukast is a selective leukotriene receptor antagonist. It israpidly absorbed after oral administration and has abioavailability > 60% of the administered dose. Half-life is4 -- 5 h and it is metabolized in the liver to several metaboliteswhich are mainly excreted in bile [79]. Although it wasaccepted that the major enzymes involved in montelukast bio-disposition were CYP2C9 and CYP3A4 [80], association ofcommon polymorphisms in CYP3A4 and CYP2C9 geneswith response to montelukast were analyzed with negativeresults [81]. A re-evaluation of montelukast metabolism hasindicated a major role for CYP2C8 in montelukast biodispo-sition [82,83]. In addition, montelukast is a selective CYP2C8inhibitor [84]. Because of the recent confirmation of the majorimplication of CYP2C8 in montelukast biodisposition,because CYP2C8 accounts for 70 -- 80 % of total metabolismand because common loss-of-function CYP2C8 polymor-phisms occur in all major human ethnicities [85], further stud-ies on the impact of CYP2C8 gene variation on montelukasttoxicity and clinical response are warranted.

2.5.5 OmalizumabOmalizumab is a monoclonal antibody that selectively bindsto all forms of circulating IgE, thus preventing their bindingto the IgE receptor. It is administered subcutaneouslyand the peak serum concentration is reached after 7 -- 8

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days [86]. This drug is most likely removed by opsonizationand therefore no metabolic implications apply.

3. Genetic variations that can modify themetabolism of drugs used in the treatmentof ADs

Because many of the drugs used in the treatment of ADs areextensively metabolized, it is conceivable that geneticallydetermined alterations in drug metabolism may affect theclinical response to these drugs. Impaired metabolism maycause drug accumulation, thereby facilitating the occurrenceof adverse effects, or it may cause therapeutic failure if pro-drugs are not efficiently converted to their active forms.Increased metabolism (as occurs in carriers of functionalCYP2D6 gene duplications or carriers of the gain-of-functionCYP3A5*1 or CYP2C91*17 alleles) may cause differences inpresystemic metabolism. Table 1 summarizes the major varia-tions in CYP genes which are relevant for drugs used in thetreatment of ADs. Because the functional effect of mostCYP alleles are well understood, variant alleles with no func-tional consequences have been excluded. In addition, onlyvariant alleles with an allele frequency ‡ 0.001, according tothe 1000 genomes catalog [87], are reported. Further detailson rare CYP alleles and their functional consequences are

available on the website [88]. CYP1A1 has common functionalvariations, and among these the most common is that desig-nated as CYP1A1*2, which has been associated with severaldisorders related to the metabolism of polycyclic aromatichydrocarbons. Regarding the CYP2C8 polymorphisms, themost relevant SNPs are reported in Table 1. Variations inthe CYP2C8 gene are unambiguously related to alteredmetabolism and to adverse drug reactions, CYP2C8 being ofparticular importance in the metabolism of nonsteroidalanti-inflammatory drugs (for a review, see Refs. [89,90].) andanticancer drugs. With regard to drugs used in the treatmentof ADs, CYP2C8 plays a relevant role in the metabolism ofmontelukast and it is likely that common gene variationswould significantly modify the response to this drug. In addi-tion to genetic polymorphisms, CYP2C8 activity can beinhibited by several drugs and induced by CYP2C8 sub-strates [91], and hence it is conceivable that altered montelu-kast metabolism would occur in individuals receivingsubstrates, inducers or inhibitors of this enzyme (for a detailedlist of these substances, see Ref. [51]). CYP2C19 has two com-mon loss-of-function variants, designated as CYP2C19*2 andCYP2C19*3 and one gain-of-function variant designatedas CYP2C19*17. In the case of CYP2D6, > 100 genevariants have been identified [88]. Among these, common non-functional variations with allele frequencies over 1% in at leastone ethnic group include CYP2D6*3, *4, *5 and *6. In

Table 1. Major CYP450 gene variations for enzymes involved in the metabolism of drugs in the treatment of ADs.

SNP id Chromosome:

base pair

Gene Type Effect (IUPAC-IUB

amino acid notation)

Minor allele

frequency

Variant allele

identification

rs28399430 15:75012894 CYP1A1 Nonsynonymous P/R 0.001 CYP1A1*11rs56240201 15:75012940 CYP1A1 Nonsynonymous R/W 0.001 CYP1A1*10rs41279188 15:75012979 CYP1A1 Nonsynonymous R/S 0.001 CYP1A1*5rs1048943 15:75012985 CYP1A1 Nonsynonymous I/L 0.120 CYP1A1*2rs1799814 15:75012987 CYP1A1 Nonsynonymous T/N 0.015 CYP1A1*4rs10509681 10:96798749 CYP2C8 Nonsynonymous K/R 0.065 CYP2C8*3rs11572103 10:96818106 CYP2C8 Nonsynonymous I/F 0.039 CYP2C8*2rs1058930 10:96818119 CYP2C8 Nonsynonymous I/M 0.026 CYP2C8*4rs11572080 10:96827030 CYP2C8 Nonsynonymous R/K 0.065 CYP2C8*3rs12248560 10:96521657 CYP2C19 Upstream -- 0.152 CYP2C19*17rs4986893 10:96540410 CYP2C19 Nonsynonymous Stop gained 0.014 CYP2C19*3rs4244285 10:96541616 CYP2C19 Synonymous -- 0.199 CYP2C19*2-- -- CYP2D6 Gene deletion -- 0.025 CYP2D6*5-- -- CYP2D6 Gene duplication -- 0.035 CYP2D6xNrs28371725 22:42523805 CYP2D6 Intronic Splice site variant 0.055 CYP2D6*41rs5030656 22:42524176 -- 42524178 CYP2D6 Nonsynonymous K/-- 0.011 CYP2D6*9rs35742686 22:42524244 CYP2D6 Frameshift R/G 0.010 CYP2D6*3rs3892097 22:42524947 CYP2D6 Intronic Splice site variant 0.011 CYP2D6*4rs5030655 22:42525086 CYP2D6 Nonsynonymous W/G 0.010 CYP2D6*6rs1065852 22:42526694 CYP2D6 Nonsynonymous P/S 0.255 CYP2D6*10rs56053398 1:60370710 CYP2J2 Nonsynonymous D/N 0.001 CYP2J2*5rs66515830 1:60377389 CYP2J2 Nonsynonymous I/N 0.001 CYP2J2*4rs35599367 7:99366316 CYP3A4 Intronic -- 0.021 CYP3A4*22rs2740574 7:99382096 CYP3A4 Upstream -- 0.202 CYP3A4*1Brs41303343 7:99250394 -- 99250393 CYP3A5 Frameshift -- 0.029 CYP3A5*7rs56411402 7:99262860 CYP3A5 Downstream -- 0.001 CYP3A5*4rs776746 7:99270539 CYP3A5 Intronic Splice site variant 0.313 CYP3A5*3

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Table 2. Polymorphisms in genes coding for glucocorticoid-metabolizing enzymes.

SNP id Chromosome:

base pair

Gene Type Effect (IUPAC-IUB

amino acid notation)

Minor allele

frequency

rs248793 5:6633779 SRD5A1 Nonsynonymous A/G 0.449rs248805 5:6645016 SRD5A1 Nonsynonymous T/A 0.452rs8192179 5:6645044 SRD5A1 Nonsynonymous C/Y 0.037rs180764167 5:6645137 SRD5A1 Nonsynonymous T/M 0.001rs8192181 5:6645158 SRD5A1 Nonsynonymous Y/C 0.037rs8192182 5:6645163 SRD5A1 Nonsynonymous V/I 0.012rs186093099 5:6651952 SRD5A1 Intronic Splice site variant 0.003rs140569241 5:6652043 SRD5A1 Nonsynonymous G/S 0.005rs2307268 5:6652129 SRD5A1 Intronic Splice site variant 0.008rs8192208 5:6656207 SRD5A1 Nonsynonymous N/D 0.002rs3736316 5:6656210 SRD5A1 Nonsynonymous G/R 0.320rs200640087 5:6662923 SRD5A1 Intronic Splice site variant 0.001rs9332965 2:31754379 SRD5A2 Intronic Splice site variant 0.002rs187135488 2:31754530 SRD5A2 Intronic Splice site variant 0.001rs190907624 7:137761319 AKR1D1 Nonsynonymous P/S 0.001rs199535210 7:137773486 AKR1D1 Nonsynonymous R/Q 0.001rs182534921 7:137776506 AKR1D1 Intronic Splice site variant 0.001rs144365681 7:137776507 AKR1D1 Intronic Splice site variant 0.003rs187887082 7:137776584 AKR1D1 Nonsynonymous L/P 0.001rs201702426 7:137776608 AKR1D1 Nonsynonymous I/T 0.001rs201142773 7:137776636 AKR1D1 Intronic Splice site variant 0.001rs201081358 7:137782689 AKR1D1 Nonsynonymous E/D 0.001rs201408607 7:137791429 AKR1D1 Nonsynonymous Y/H 0.001rs186764354 7:137791937 AKR1D1 Intronic Splice site variant 0.001rs182820353 7:137792268 AKR1D1 Nonsynonymous R/Q 0.001rs116226492 7:137798500 AKR1D1 Nonsynonymous R/H 0.001rs201918644 7:137801363 AKR1D1 Intronic Splice site variant 0.001rs149693250 10:5008137 AKR1C1 Nonsynonymous K/R 0.004rs200176428 10:5008148 AKR1C1 Nonsynonymous E/K 0.001rs201114964 10:5008217 AKR1C1 Nonsynonymous Stop gained 0.001rs200396686 10:5009115 AKR1C1 Intronic Splice site variant 0.001rs139089923 10:5009137 AKR1C1 Nonsynonymous Stop gained 0.001rs200730776 10:5009203 AKR1C1 Nonsynonymous L/V 0.001rs184667460 10:5009230 AKR1C1 Nonsynonymous V/I 0.001rs113645163 10:5011006 AKR1C1 Intronic Splice site variant 0.007rs202231968 10:5011143 AKR1C1 Intronic Splice site variant 0.006rs201500205 10:5019931 AKR1C1 Nonsynonymous Stop gained 0.001rs187772495 10:5032222 AKR1C2 Nonsynonymous G/V 0.001rs199669245 10:5034015 -- 5034018 AKR1C2 Intronic Splice site variant 0.009rs201188346 10:5040811 AKR1C2 Intronic Splice site variant 0.001rs200908381 10:5040894 AKR1C2 Nonsynonymous V/M 0.001rs200244668 10:5040909 AKR1C2 Nonsynonymous A/S 0.001rs141880056 10:5042631 AKR1C2 Nonsynonymous W/R 0.001rs145967531 10:5042747 AKR1C2 Nonsynonymous V/I 0.001rs187468986 10:5042839 AKR1C2 Nonsynonymous R/Q 0.001rs142672563 10:5043747 AKR1C2 Nonsynonymous D/H 0.002rs147648222 10:5043749 AKR1C2 Nonsynonymous A/V 0.003rs201200808 10:5043791 AKR1C2 Nonsynonymous N/S 0.001rs2854482 10:5043821 AKR1C2 Nonsynonymous F/Y 0.051rs1937866 10:5049595 AKR1C2 Intronic Splice site variant 0.499rs184594447 10:5120064 AKR1C3 Intronic Splice site variant 0.002rs182276605 10:5123865 AKR1C3 Intronic Splice site variant 0.001rs183569513 10:5136640 AKR1C3 Nonsynonymous D/Y 0.001rs12529 10:5136651 AKR1C3 Nonsynonymous H/Q 0.428rs145911457 10:5138663 AKR1C3 Nonsynonymous I/T 0.001rs35961894 10:5138714 AKR1C3 Nonsynonymous R/Q 0.024rs11551177 10:5138747 AKR1C3 Nonsynonymous E/G 0.047rs200981816 10:5139642 AKR1C3 Nonsynonymous H/R 0.001

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addition, variants leading to reduced function with allele fre-quencies over 1% in at least one ethnic group includeCYP2D6*9 or *10. CYP2D6 gene duplication or amplifica-tion exists with high interethnic variability [92]. In contrastwith CYP2D6, functional variations affecting the CYP2J2gene, which codes for the major enzyme involved in themetabolism of ebastine, are extremely rare (Table 1). Withregard to CYP3A4, over 20 variant alleles have beendescribed, but, although evidence for functional consequenceswith the variant alleles CYP3A4*1B and CYP3A4*22 havebeen reported, these variant alleles do not seem to be suffi-cient to explain the variability in CYP3A4 metabolism [50,91].In contrast, the genetic basis for CYP3A5 metabolism are wellknown and widely studied.Gene variations on enzymes metabolizing glucocorticoids

are shown in Table 2. The action of glucocorticoids can be ter-minated by converting them into biologically inactive forms,in complex metabolic processes which involve a number ofenzymes and tissues. The metabolic reactions involved includereduction and oxidation. Reduction reactions are involved in

the production of the majority of urinary glucocorticoidmetabolites in urine. Two major reduction reactions occur:reduction of the cortisol A ring double bond, carried out by5 a- and 5-b reductases, which are encoded by the genesSRD5A1 (5 a-reductase type 1), SRD5A2 (5 a-reductasetype 2) and AKR1D1 (5 b-reductase) [93], and reduction ofthe keto group, carried out by 3 a-hydroxysteroid dehydro-genase [94]. Four soluble human 3 a-hydroxysteroid dehydro-genase isoforms exist, encoded by the genes AKR1C1 toAKR1C4. Reduced metabolites can undergo further reductionat the 20-ketone by 20-hydroxysteroid dehydrogenases.Reduction can also be carried out by 11 b-hydroxysteroiddehydrogenase type I (HSD11B1), which has both dehydro-genase and reductase activities, and metabolize steroids to anextent which is strongly dependent on substrate structure [56].

Table 2 shows gene variations with putative functional sig-nificance and with variant allele frequencies ‡ 0.001 [87] ingenes coding for glucocorticoid-metabolizing enzymes. Thegenes coding for the 5-reductases show large differences ingenetic variability: while SRD5A2 shows little variation,

Table 2. Polymorphisms in genes coding for glucocorticoid-metabolizing enzymes (continued).

SNP id Chromosome:

base pair

Gene Type Effect (IUPAC-IUB

amino acid notation)

Minor allele

frequency

rs118150330 10:5139644 AKR1C3 Nonsynonymous Stop gained 0.001rs12387 10:5139685 AKR1C3 Nonsynonymous K/N 0.132rs190674338 10:5139690 AKR1C3 Nonsynonymous A/V 0.001rs201680078 10:5139709 AKR1C3 Nonsynonymous D/E 0.001rs28943579 10:5141058 AKR1C3 Nonsynonymous C/Y 0.005rs192314534 10:5141520 AKR1C3 Nonsynonymous A/V 0.001rs200514658 10:5141559 AKR1C3 Nonsynonymous I/T 0.001rs34186955 10:5141609 AKR1C3 Nonsynonymous P/S 0.012rs61730879 10:5141619 AKR1C3 Nonsynonymous K/M 0.002rs140580498 10:5141639 AKR1C3 Nonsynonymous Stop gained 0.001rs147205859 10:5141642 AKR1C3 Intronic Splice site variant 0.002rs139146411 10:5144318 AKR1C3 Nonsynonymous R/Q 0.001rs116351688 10:5144345 AKR1C3 Nonsynonymous S/L 0.001rs139129999 10:5144674 AKR1C3 Intronic Splice site variant 0.001rs201848142 10:5144760 AKR1C3 Nonsynonymous I/T 0.001rs62621365 10:5144768 AKR1C3 Nonsynonymous R/C 0.037rs201226170 10:5144816 AKR1C3 Nonsynonymous E/K 0.037rs199763655 10:5147830 AKR1C3 Nonsynonymous D/V 0.001rs34320249 10:5149649 AKR1C3 Intronic Splice site variant 0.057rs3812617 10:5238283 AKR1C4 Intronic Splice site variant 0.112rs191144263 10:5242255 AKR1C4 Nonsynonymous Stop gained 0.001rs139370478 10:5242286 AKR1C4 Nonsynonymous R/T 0.001rs11253043 10:5247754 AKR1C4 Nonsynonymous G/E 0.027rs3829125 10:5247784 AKR1C4 Nonsynonymous S/C 0.103rs139905834 10:5248257 AKR1C4 Nonsynonymous D/V 0.001rs117650600 10:5254583 AKR1C4 Nonsynonymous E/A 0.001rs199533218 10:5254611 AKR1C4 Nonsynonymous K/N 0.001rs201810043 10:5254633 AKR1C4 Nonsynonymous K/E 0.001rs140450651 10:5255003 AKR1C4 Nonsynonymous G/A 0.007rs4880718 10:5255025 AKR1C4 Nonsynonymous Q/R 0.001rs17134592 10:5260682 AKR1C4 Nonsynonymous L/V 0.103rs41283130 1:209879288 HSD11B1 Intronic Splice site variant 0.001rs202219444 1:209879292 HSD11B1 Intronic Splice site variant 0.001rs200360270 1:209880338 HSD11B1 Nonsynonymous L/I 0.001

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SRD5A1 is highly polymorphic and common nonsynony-mous variations occur. Of these, the rs3736316 polymor-phism is common and is predicted as deleterious by usingthe SIFT algorithm. Another SRD5A1 SNP predicted as del-eterious with SIFT and PolyPhen-2 is rs140569241, althoughthe allele frequency is low (Table 2). The rest of the SRD5A1nonsynonymous SNPs are predicted as benign. With regardto the AKR1D1 gene, virtually all nonsynonymous SNPshave a high deleterious effect according to SIFT and Poly-Phen-2, although these gene variants are extremely rare(Table 2). High predicted functional impact and low allele fre-quencies are also observed for AKR1C1 gene variants. Theonly exception is the nonsynonymous SNP rs2854482, whichshows a frequency of over 5% and is predicted as benignaccording to SIFT and PolyPhen-2. AKR1C3 is by far themost variable AKR1C gene. Besides two stop-gained SNPs,which occur at a low frequency, common nonsynonymousSNPs occur in this gene. The two SNPs which occur withthe highest frequencies, namely rs12529 and rs12387, are pre-dicted as benign according to SIFT and PolyPhen-2. How-ever, the SNPs rs11551177 and rs62621365 show allelefrequencies of over 3% and are predicted as deleterious.A similar situation is observed with AKR1C4: thers11253043 SNP has a frequency of over 2.5% and is pre-dicted as deleterious, whereas common nonsynonymousSNPs, such as rs17134592 or rs3829125, are predicted asbenign. The only SNP with an allele frequency of > 0.001in the HSD11B1 gene is also predicted as benign. In sum-mary, rare gene variants with a high functional impact havebeen described for all these genes. Nevertheless, new function-ally relevant gene variations and their functional and clinicalconsequences are still being described [95,96].

These gene variants can modify the metabolism of gluco-corticoids used in the management of ADs. In addition, therole of regulatory mechanisms in glucocorticoid metabolismand signaling, for instance microRNAs, is a promising fieldthat requires further research [97]. The occurrence of func-tional copy number variations (CNVs) in genes coding for

glucocorticoid-metabolizing enzymes may modify the metab-olism and hence the clinical response to these drugs. Althoughthe occurrence of CNVs for the genes has not been investi-gated in detail, a duplication of the SRD5A2 gene has beendescribed in a patient with gonadal dysgenesis [98]. Furtherstudies on CNVs and microRNAs with regard to the clinicalresponse to glucocorticoids are warranted.

Table 3 shows common gene variations in other enzymesinvolved in the metabolism of drugs which are used in thetreatment of ADs. COMT gene variations with putativefunctional significance and with variant allele frequencies‡ 0.001 are shown. Of these SNPs, it has been shown thatthe rs4680 polymorphism, which is a relatively commonone, is related to altered enzyme activity because amino acidsubstitution leads to changes in thermolability [99]. Putativefunctional variants in the MAOA and MAOB genes are rare(Table 3), and no SNPs with putative functional consequen-ces, that is, missense, stop gain or stop loss, frameshift, spliceregion variants or transcript ablation, have been identifiedin the SULT1A3 genes according to the 1000 genomescatalog [87].

4. Conclusion

This review focuses on drugs frequently used in ADs. Most ofthese drugs used are extensively metabolized in humans, thegenes coding for enzymes involved in the metabolism ofmost of these drugs are highly variable and common func-tional polymorphisms for some of these genes have been iden-tified. Several examples highlight the importance of themetabolism of these drugs in the management of ADs. Poly-morphic drug metabolism is a relevant factor in the pharma-cokinetics or in the clinical response to many of these drugsand inhibition of drug metabolism has been associated withaltered clinical response for these drugs. Personalized therapy,taking into consideration these gene variations, as well as theconcomitant use of other enzyme substrates, inhibitors orinducers, may help to prevent adverse reactions and to

Table 3. Common gene variations in other enzymes which modify the metabolic activity of drugs in the treatment

of ADs.

SNP id Chromosome:

base pair

Gene Type Effect (IUPAC-IUB

amino acid notation)

Minor allele

frequency

rs6267 22:19950263 COMT Nonsynonymous A/S 0.017rs76452330 22:19950329 COMT Nonsynonymous D/N 0.003rs5031015 22:19951103 COMT Nonsynonymous A/T 0.002rs4680 22:19951271 COMT Nonsynonymous V/M 0.389rs4646315 22:19951897 COMT Nonsynonymous K/N 0.166rs4646318 22:19954847 COMT Nonsynonymous R/K 0.056rs199524208 X:43571977 MAOA Nonsynonymous A/V 0.001rs58524323 X:43587431 MAOA Nonsynonymous R/Q 0.002rs182018652 X:43626077 MAOB 3 prime UTR -- 0.002rs3027441 X:43626868 MAOB Intronic Splice site variant 0.108rs148113949 X:43627893 MAOB Intronic -- 0.011

Metabolic considerations of drugs in the treatment of AD

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optimize therapy. It should be borne in mind that the metab-olism of some oral drugs might be influenced by meal. Forinstance, it is well known that food components, such asgrapefruit juice or St John’s Wort modify CYP3A activity,and hence the presystemic metabolism of drugs metabolizedby CYP3A (see above) may be greatly influenced by meal.However, the metabolic implications for many drugs used inADs are far from being completely understood, and furtherstudies are required to obtain a complete view of the meta-bolic implications, and as to how we can use the informationon variability in the corresponding metabolic pathways toimplement the pharmacological management of ADs.

5. Expert opinion

Drug metabolism is a major factor that determines clinicalresponse. With regard to drugs used in the treatment of ADs,impaired metabolism may cause drug accumulation, therebyfacilitating the occurrence of adverse effect, or it may causetherapeutic failure if prodrugs are not efficiently converted totheir active forms. Increased metabolism (as occurs in carriersof functional CYP2D6 gene duplications or carriers of thegain-of-function CYP3A5*1 or CYP2C91*17 alleles) may causedifferences in presystemic metabolism. Although guidelinesand gene/drug pairs have been identified for several drugs, espe-cially for anticancer drugs and other drugs which show hightoxicity or severe adverse effects [12,100], no such guidelines orpharmacogenomic recommendations have been formulated sofar for drugs used in the treatment of ADs. When combiningdifferent drugs, as is often done in allergic patients, one hasto make some considerations based on the fact that many drugsbelonging to distinct therapeutical groups may interact. Forinstance, the combination oral antihistamines + b-2-adrenergicreceptor agonist + glucocorticoids may include drugs which areCYP3A4/5 substrates and/or inhibitors in all drug categories(see above). Avoiding combinations of drugs which can modifythe metabolism of each other would be desirable.Key findings in this field are the identification of the major

enzymes involved in the metabolism of these drugs and inmost cases the identification of major functional polymor-phisms in the genes coding for these enzymes, particularlyCYP2C8, CYP2C19, CYP2D6, CYP2J2, CYP3A4 andCYP3A5 genes. Less understood are the effects of polymor-phisms in the genes COMT, MAOA, MAOB, as well as genesinvolved in the biotransformation of glucocorticoids, namelySRD5A1 and 2, AKR1D1, AKR1C1 to 4 and HSD11B1.The 1000 genomes project constituted a milestone in theidentification of gene variants and holds great promise forthe future implementation of gene/drug pairs and guidelinesfor the use of drugs in the treatment of ADs.Major weaknesses include the lack of sufficient clinical

studies analyzing the impact in vivo of these gene variationsin drug metabolism, pharmacokinetics or response, the lackof sufficient genetic studies to assess interethnic and intra-ethnic variability for most of the mentioned genes, very little

information on CNV and gene rearrangements, with theexception of CYP2D6, and the so far negative search forgenetic variants with high phenotype-predictive capacity forthe CYP3A4 enzyme, which is crucial in the metabolism ofdrugs used in the treatment of ADs.

Further studies are required to obtain a complete view ofthe metabolism of these drugs. The major enzymes involvedin the metabolism of some widely used drugs remains to beidentified. In many cases where several enzymes have beenshown to be involved in the metabolism of a determineddrug, the quantitative importance of each of these enzymesin the in vivo metabolism remains to be assessed, as a substan-tial part of the available information has been obtainedin vitro or in animal models.

Among research areas which are of interest at present, keypoints that have not been investigated in detail are the vari-ability of presystemic metabolism, particularly for drugswhich are administered as inhalants. Because CYP3A5 is themajor CYP3A form in the lung, and because many inhaleddrugs suffer presystemic metabolism, it is conceivable that car-riers of the gain-of-function CYP3A5*1 allele may have lowtherapeutic efficacy, or apparent resistance to inhaled drugsthat are CYP3A substrates; individuals homozygous for theCYP3A5*1 allele account for about 10% of individuals andare considered as high enzyme expressers.

Another relevant issue that may be explained, at least inpart, by metabolic variability is the resistance to some drugsused in the treatment of ADs. This is a relatively commonphenomenon which is likely to be influenced by metabolicvariability and which deserves further investigation to eluci-date whether unusual pharmacokinetic profiles occur in indi-viduals who show resistance and whether variations in genescoding for the enzyme(s) involved in the biotransformationof the corresponding drug cosegregate with the nonresponderphenotypes. If, as expected, genotype/phenotype associationsare identified, pre-prescription genetic tests may help inselecting alternative drugs or in recommending changes indrug dosing, as occurs with many drugs which undergopolymorphic metabolism. These studies hold great promisefor the future implementation of a safer and more efficientmanagement of drugs used in the treatment of ADs.

Acknowledgment

The authors are grateful to James McCue for his assistance inlanguage editing.

Declaration of interest

The authors’ laboratory work is financed by Grants PS09/00943, PS09/00469, PI12/00241, PI12/00324 and RETICSRD12/0013/0002 from Fondo de Investigacion Sanitaria,Instituto de Salud Carlos III, Spain and GR10068 from Juntade Extremadura, Spain. The authors also declare financialsupport from FEDER funds from the European Union.

E. Garcıa-Martın et al.

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AffiliationElena Garcıa-Martın†1,2 MD PhD,

Gabriela Canto2,3 & Jose AG Ag�undez2,4

†Author for correspondence1University of Extremadura,

Department of Biochemistry &

Molecular Biology,

Avda. de la Universidad s/n,

E-10071, Caceres, Spain

Tel: +34927257000 ext 89676;

E-mail: elenag@unex.es2Red de Investigacion de Reacciones

Adversas a Alergenos y Farmacos (RIRAAF),

Madrid, Spain3Hospital Infanta Leonor,

Service of Allergy, Madrid, Spain4University of Extremadura,

Department of Pharmacology,

Caceres, Spain

E. Garcıa-Martın et al.

1452 Expert Opin. Drug Metab. Toxicol. (2013) 9(11)

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