Comparison of the Contributions of Cytochromes P450 3A4 ...jhs.pharm.or.jp/data/56(3)/56_239.pdf · P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those

Journal of Health Science, 56(3) 239–256 (2010) 239

— Review —

Comparison of the Contributions of Cytochromes P450 3A4and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Toshiro Niwa, Norie Murayama, and Hiroshi Yamazaki∗

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3–3165, Higashi-tamagawa Gakuen,Machida 194–8583, Japan

(Received March 12, 2010; Accepted March 31, 2010; Published online March 31, 2010)

A meta-analysis was performed on the reported literature regarding followings. First, values of the Michaelis-Menten constants (Km), maximal velocities (Vmax), and intrinsic clearance (Vmax/Km) and the metabolic activitiesmediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (Ki); and third, maximuminactivation rate constants (kinact) to establish the contribution of P450 3A5 to drug metabolism. At least 120of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of Km, Vmax, and Vmax/Kmvalues were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In14–18% of the metabolic reactions, the Vmax and Vmax/Km values for P450 3A5 were more than twice those forP450 3A4. The Ki values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P4503A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism andadverse drug interactions.

Key words —— cytochrome P450 3A5, cytochrome P450 3A4, meta-analysis, metabolic activity, inhibition con-stant, mechanism-based inhibition

INTRODUCTION

Cytochrome P450 (P450 or CYP) 3A is themost important human P450 subfamily due to itshigh relative abundance in the liver and broad sub-strate specificity.1–3) CYP3A4 is generally thoughtto be the predominant form expressed in the hu-man liver and intestine, whereas CYP3A5, whichis expressed polymorphically, might contribute asmuch as 50% of hepatic CYP3A in a third of Cau-casians and in one half of African-Americans.4)

Since CYP3A5 and CYP3A4 are 83% homoge-neous in terms of amino acid sequence, it is believedthat the substrate specificity of CYP3A5 is simi-lar to that of CYP3A4; however, certain differencesin catalytic properties have been demonstrated.2, 5)

Similarly, many of the inhibitors of CYP3A4 are re-ported to also inhibit CYP3A5 activities.6)

∗To whom correspondence should be addressed: Laboratory ofDrug Metabolism and Pharmacokinetics, Showa Pharmaceuti-cal University, 3–3165, Higashi-tamagawa Gakuen, Machida194–8583, Japan. Tel. & Fax: +81-42-721-1406; E-mail:[email protected]

Recently we summarized the reported values ofthe Michaelis-Menten constants (Km), maximal ve-locities (Vmax), and intrinsic clearance (Vmax/Km)mediated by CYP3A4 and/or CYP3A5, as well asthe inhibition constants (Ki), 50% inhibitory con-centrations (IC50), and maximum inactivation rateconstants (kinact), and demonstrated that while thesubstrate specificities of CYP3A4 and CYP3A5generally overlap, they are somewhat different.7)

However, there are few reports that compare in de-tail the kinetic parameters for drug oxidation and thesubstrate inhibition potential of metabolic reactionsmediated by CYP3A4 and CYP3A5.

In this review, values for metabolic activitiestaken from the literature are compared in additionto the kinetic parameters to predict the relative con-tribution of CYP3A5. The kinetic parameters usedin this study were taken from the review submittedin 2007 by us7) as well as from more recent reports.For drug oxidation rates, a comprehensive literaturesearch was performed to investigate the Km (µM),Vmax (nmol/min per nmol P450), and/or Vmax/Km(ml/min per nmol P450) values for recombinant ex-

C©2010 The Pharmaceutical Society of Japan

240 Vol. 56 (2010)

pressed CYP3A4 or CYP3A5. Because only fullkinetic profiles provide detailed information on theaffinity of an enzyme for particular compounds,the metabolic activities of CYP3A4 and CYP3A5were investigated separately from these kinetic pa-rameters. In this article, the literature compar-ing metabolic activities was also investigated; thiswas not the case in our previous review.7) Kineticparameters estimated by substrate deletion activi-ties were excluded. It was mostly the case that:data were generated with baculovirus-infected in-sect cells (e.g., Supersomes or Baculosomes) or Es-cherichia coli expressing CYP3A4 or CYP3A5, itwas not stated whether cytochrome b5 was added orhow much CYP reductase was coexpressed, or esti-mation of the free fraction in microsomal incubationwas not carried out. For inhibition potency, Ki andkinact, but not IC50, were investigated. When the de-sired CYP3A5/CYP3A4 ratios were not given, thecorresponding ratios were calculated from the ki-netic parameters given in the article.

METABOLIC ACTIVITY OF CYP3A4AND CYP3A5

Seven metabolic reactions have been shown tobe catalyzed by CYP3A4 but not by CYP3A5, and 6of the 7 reactions were hydroxylation (Table 1).8–12)

However, in these reactions, a minor contribution ofCYP3A5 may be demonstrated in the future whendetection methods for the metabolite have been im-proved. In contrast, reactions which are predom-inantly catalyzed by CYP3A5 have not been re-ported.

The Km, Vmax, and Vmax/Km values formetabolic reactions mediated by CYP3A5 werecompared with those mediated by CYP3A4 (Ta-ble 2).13–53) The kinetic parameters of 73 metabolicreactions (56 substrates) catalyzed both by CYP3A4and by CYP3A5 have been reported. For these 73

Table 1. Metabolic Reactions Catalyzed by CYP3A4 but Not by CYP3A5

Substrate Reaction ReferencesCarebastine Dealkylation Liu et al. (2006)8)

CP-195,543 Hydroxylation at benzylic position (M1 formation) Khojasteh-Bakht et al. (2003)9)

CP-195,543 Hydroxylation at benzylic position (M2 formation) Khojasteh-Bakht et al. (2003)9)

CP-195,543 Aromatic hydroxylation (M3 formation) Khojasteh-Bakht et al. (2003)9)

Cyclosporine C-Hydroxylation (AM1 formation) Dai et al. (2004)10)

Fluvastatin 5-Hydroxylation Fischer et al. (1999)11)

Itraconazole Hydroxylation Isoherranen et al. (2004)12)

metabolic reactions, the mean (± S.D.) CYP3A5/CYP3A4 ratios of Km, Vmax, and Vmax/Km val-ues were 1.93± 2.40, 1.25± 1.59, and 1.20± 1.99,respectively, but the median ratios were 1.17,0.64, and 0.56, respectively. In addition, therewere 47 reactions in which both CYP3A4 andCYP3A5 catalyzed the metabolic reactions, but Km,Vmax, and Vmax/Km values were not investigated(Table 3).54–73) The mean (± S.D.) and medianCYP3A5/CYP3A4 ratios of the metabolic activitiesin these 47 reactions were 0.69± 1.23 and 0.28, re-spectively.

Among the psychotropic drugs, both the Vmaxand Km values of CYP3A5 for the 1′-hydroxylationof alprazolam and midazolam were more than twicethose of CYP3A4; however, the Vmax/Km values ofCYP3A5 were comparable with or higher than thoseof CYP3A4 (Table 2). In contrast, the Km values,but not the Vmax values, of CYP3A5 for the 1′-hydroxylation of triazolam and 4-hydroxylation ofalprazolam, midazolam, and triazolam, were com-parable with those of CYP3A4, and the Vmax/Kmvalues of CYP3A5 were comparable with thoseof CYP3A4, except that the Vmax/Km value ofCYP3A5 for midazolam 4-hydroxylation was lowerthan that of CYP3A4. Thus, differences in affinityand metabolic capacity do not appear to depend onthe chemical structures of the substrate and/or thereaction position.

The Vmax/Km values for anticancer drugs me-diated by CYP3A5 are comparable with or greaterthan those mediated by CYP3A4. In contrast,most of the Vmax and Vmax/Km values for dehy-drogenation of many of the dihydropyridine cal-cium antagonists, such as benidipine, felodipine,and nifedipine, and steroid hydroxylation, suchas testosterone 6β-hydroxylation and estradiol 2-or 4-hydroxylation, mediated by CYP3A5, arelower than those mediated by CYP3A4, whereasthe Km values for CYP3A5 are higher than thosefor CYP3A4.20, 27–29, 41) Similarly, the CYP3A5-

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Table 2. Comparison of Kinetic Parameters for Metabolic Reactions Catalyzed by CYP3A4 and CYP3A5

Substrate Reaction n Ratio (CYP3A5/CYP3A4) ReferencesKm Vmax Vmax /Km

Anesthetics Lidocaine N-Demethylation 1 0.28 0.38 1.35 Huang et al.(2004)13)

Anticonvulsants Carbamazepine 10,11-Epoxidation 2 2.51(1.36 – 3.65)

1.56(1.23 – 1.89)

0.91(0.90 – 0.93)

Huang et al.(2004),13) Henshallet al. (2008)14)

Zonisamide 2-Sulfamoylacetyl-phenol formation

1 0.72 0.14 0.19 Nakasa et al.(1998)15)

Antibiotics,macrolide

Erythromycin N-Demethylation 1 2.09 0.86 0.41 Huang et al.(2004)13)

Antifungals, azole Fluconazole 3-Hydroxylation 1 0.47 0.20 0.35 Huang et al.(2004)13)

Fluconazole Demethylation 1 1.23 0.39 0.20 Huang et al.(2004)13)

Antiprotozoals,Antimalarials

β-Arteether O-Deethylation 1 0.59 0.22 0.37 Grace et al.(1998)16)

Artelinic acid O-Debenzylation 1 1.85 1.84 0.99 Grace et al.(1999)17)

Quinine 3-Hydroxylation 1 2.15 3.19 1.44 Allqvist et al.(2007)18)

Calcium antago-nists

Diltiazem N-Demethylation 3 3.86± 1.86(1.73 – 5.09)

3.35± 0.94(2.32 – 4.17)

1.21± 1.09(0.46 – 2.46)

Jones et al.(1999),19) Williamset al. (2002),20)

Yamaori et al.(2005)21)

R-Verapamil N-Demethylation 1 0.88 0.29 0.33 Shen et al. (2004)22)

R-Verapamil N-Dealkylation 1 0.54 0.14 0.25 Shen et al. (2004)22)

S -Verapamil N-Demethylation 1 0.59 0.20 0.34 Shen et al. (2004)22)

S -Verapamil N-Dealkylation 1 0.35 0.09 0.24 Shen et al. (2004)22)

Cancer chemother-apy

Erlotinib O-Demethylation 1 5.46 2.57 0.56 Li et al. (2007)23)

Etoposide O-Demethylation 1 0.18 0.06 0.35 Zhuo et al. (2004)24)

Ifosfamide N-Dechloroethyla-tion

1 0.59 1.76 3.0 McCune et al.(2005)25)

Tamoxifen N-Demethylation 1 0.48 0.60 1.25 Williams et al.(2002)20)

Vincristine M1 formation (de-hydrogenation)

1 0.73 9.00 12.39 Minus cytochromeb5. Dennison et al.(2006)26)

Cold and allergyagents:antihistamines

Dextromethorphan N-Demethylation 1 — — 1.07 CYP3A5: does notreach apparent satu-ration within thesubstrate concentra-tion used. Huang etal. (2004)13)

Ebastine Dealkylation 1 0.72 0.22 0.30 Liu et al. (2006)8)

Ebastine Hydroxylation 1 0.34 1.17 3.00 Liu et al. (2006)8)

Hydroxyebastine Dealkylation 1 2.87 0.39 0.13 Liu et al. (2006)8)

Hydroxyebastine Carboxylation 1 3.91 0.72 0.19 Liu et al. (2006)8)

Terfenadine t-Butyl hydroxyla-tion

1 5.39 2.40 0.44 Huang et al.(2004)13)

Dihydropyridinecalciumantagonistsa)

Dihydropyridinecalciumantagonista)

Dehydrogenation 5 6.62± 9.35(0.37 – 23.0)

0.53± 0.31(0.20 – 1.01)

0.21± 0.16(0.13 – 0.85)

(See below)

242 Vol. 56 (2010)


Nifedipine Dehydrogenation 2 14.4(5.73 – 23.0)

0.72(0.42 – 1.01)

0.10(0.02 – 0.18)

Williams et al.(2002),20) Patki etal. (2003)27)

(+)-Benidipine Dehydrogenation 1 1.01 0.29 0.29 Yoon et al. (2007)28)

(−)-Benidipine Dehydrogenation 1 1.84 0.26 0.13 Yoon et al. (2007)28)Felodipine Dehydrogenation 1 1.50 0.66 0.44 Walsky and Obach

(2004)29)

HMG-CoA reduc-tase inhibitor

Atorvastatin p-Hydroxylation 1 1.24 0.53 0.42 Park et al. (2008)30)

Atorvastatin o-Hydroxylation 1 1.80 0.36 0.20 Park et al. (2008)30)

Immunosuppressa-nts

Cyclosporine C-Hydroxylation 1 7.06 4.62 0.57 Dai et al. (2004)10)

Sirolimus Hydroxylation 1 0.68 0.30 0.46 Picard et al.(2007)31)

Tacrolimus 13-O-Demethyla-tion

1 1.50 2.00 1.67 Minus cytochromeb5. Dai et al.(2006)32)

Tacrolimus 12-Hydroxylation 1 0.45 0.50 1.88 Minus cytochromeb5. Dai et al.(2006)32)

N-Methyl-D-aspartate (NMDA)antagonist

CJ-036878 Dimer (CJ-047710)formation

1 1.41 5.28 3.74 Emoto et al.(2007)33)

CJ-036878 Dimer (CJ-047713)formation

1 1.40 4.27 3.06 Emoto et al.(2007)33)

Opioids Alfentanil Piperidine N-Deal-kylation

1 0.76 0.85 1.12 Klees et al.(2005)34)

Alfentanil Amide N-dealkyla-tion

1 0.78 0.35 0.40 Klees et al.(2005)34)

Meperidine N-Demethylation 1 2.75 0.37 0.13 Ramirez et al.(2004)35)

Oxycodone N-Demethylation 1 — — 1.42 CYP3A5: did notreach apparentsaturation withinthe substrate con-centration used.Lalovic et al.(2004)36)

Phosphodiesterasetype 5 inhibitor

Sildenafil N-Demethylation 1 0.98 1.38 1.29 Ku et al. (2008)37)

Udenafil N-Dealkylation 1 0.41 0.27 0.66 Ku et al. (2008)37)

Vardenafil N-Deethylation 1 0.37 1.17 3.16 Ku et al. (2008)37)

PPARr agonist KR-62980 C-Hydroxylation 1 5.12 1.69 0.33 Kim et al. (2008)38)

KR-63198 C-Hydroxylation 1 0.06 0.46 10.00 Kim et al. (2008)38)

Psychotropics, neu-roleptics

Haloperidol Pyridinium forma-tion

1 10.94 0.50 0.05 Kalgutkar et al.(2003)39)

Psychotropics,sedative/hypnotics

Diazepam N-Demethylation 1 1.07 1.04 1.95 Galetin et al.(2004)40)

Diazepam 3-Hydroxylation 1 0.80 0.48 0.78 Galetin et al.(2004)40)

(Benzodiazepines) Flunitrazepam N-Demethylation 1 0.57 0.70 1.21 Galetin et al.(2004)40)

Flunitrazepam 3-Hydroxylation 1 0.49 1.84 2.35 Galetin et al.(2004)40)

Alprazolam 1′-Hydroxylation 2 2.40(1.57 – 3.24)

5.42(1.00 – 9.85)

2.89(0.31 – 5.48)

Williams et al.(2002),20) Galetinet al. (2004)40)

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Alprazolam 4-Hydroxylation 2 1.68(1.56 – 1.81)

1.42(0.79 – 2.05)

0.88(0.45 – 1.31)

Williams et al.(2002),20) Galetinet al. (2004)40)

Midazolam 1′-Hydroxylation 9 2.23± 0.96(0.84 – 3.98)

2.59± 0.96(1.16 – 3.86)

1.41± 0.84(0.40 – 3.05)

Williams et al.(2002),20) Patkiet al. (2003),27)

Huang et al.(2004),13) Galetinet al. (2004),40)

Yamaori et al.(2005),21) Walskyand Obach (2004),29)

Soars et al. (2006),41)

Emoto and Iwasaki(2007),42) QuintieriL. et al. (2008)43)

Midazolam 4-Hydroxylation 6 1.11± 0.90(0.20 – 2.38)

1.78± 3.31(0.21 – 8.52)

0.44± 0.23(0.18 – 0.67)

Williams et al.(2002),20) Patki etal. (2003),27)

Huang et al.(2004),13) Galetinet al. (2004),40)

Yamaori et al.(2005),21)

Quintieri et al.(2008)43)

Triazolam 1′-Hydroxylation 3 2.00± 1.47(0.82 – 3.65)

1.01± 0.76(0.49 – 1.88)

0.67± 0.53(0.18 – 1.23)

Williams et al.(2002),20) Patki et al.(2003),27) Galetinet al. (2004)40)

Triazolam 4-Hydroxylation 3 0.76± 0.10(0.64 – 0.82)

0.63± 0.40(0.35 – 1.09)

0.80± 0.42(0.55 – 1.28)

Williams et al.(2002),20) Patki et al.(2003),27) Galetinet al. (2004)40)

Steroid hormones Steroid hormoneb) Hydroxylation 10 2.97± 2.09(0.77 – 8.38)

0.49± 0.42(0.04 – 1.50)

0.18± 0.14(0.02 – 0.63)

(See below)

Testosterone 6β-Hydroxylation 7 3.37± 2.43(0.77 – 8.38)

0.64± 0.42(0.19 – 1.50)

0.29± 0.20(0.02 – 0.63)

Williams et al.(2002),20) Huanget al. (2004),13)

Patki et al. (2003),27)

Carr et al. (2006),44)

Granfors et al.(2006),45) Yamaoriet al. (2005),21)

Walsky and Obach(2004)29)

Estradiol 2-Hydroxylation 1 2.00 0.04 0.02 Williams et al.(2002)20)

Estradiol 4-Hydroxylation 1 1.93 0.11 0.06 Williams et al.(2002)20)

5-Cholestane-3,7,12-triol

25-Hydroxylation 1 2.17 0.28 0.13 Furster and Wikvall(1999)46)

244 Vol. 56 (2010)


Vasodilators Cilostazol Hydroxylation ofquinine moiety

1 0.52 0.07 0.15 Hiratsuka et al.(2007)47)

Cilostazol Hydroxylation ofhexane moiety

1 0.30 1.74 5.70 Hiratsuka et al.(2007)47)

Insecticides α-Endosulfan Sulfate formation 1 3.19 0.25 0.08 Lee et al. (2006)48)

β-Endosulfan Sulfate formation 1 0.62 0.73 1.18 Lee et al. (2006)48)

Chlorpyrifos Sulfoxide forma-tion

1 — — 0.57 Buratti et al.(2006)49)

Malathion Sulfoxide forma-tion

1 — — 0.09 Buratti et al.(2006)49)

Parathion Sulfoxide forma-tion

1 — — 0.03 Buratti et al.(2006)49)

Miscellaneousagents

BFC Dealkylation 3 1.73± 1.36(0.81 – 3.29)

0.42± 0.44(0.04 – 0.90)

0.25± 0.20(0.04 – 0.44)

Chang and Yeung(2001),50) Williamset al. (2002),20)

Carr et al. (2006)44)

DBF Dealkylation 1 2.11 2.33 1.09 Ghosal et al.(2003)51)

Territrem A 4β-C-Hydroxy-lation

1 0.96 0.16 0.17 Lin and Peng(2008)52)

TPA023 t-Butyl hydroxyla-tion

1 — — 0.70 CYP3A5: biphasic.Ma et al. (2007)53)

TPA023 N-Deethylation 1 — — 0.97 CYP3A5: biphasic.Ma et al. (2007)53)

Bold: The ratio of the parameters for CYP3A5 and CYP3A4 was less than 0.5 times or more than 2 times. a) Benidipine, felodipine, nifedipine,and nitrendipine. b) Testosterone, estradiol, and 5-cholestane-3,7,12-triol. Values in parentheses show the range (minimum – maximum). HMG: 3-hydroxy-3-methylglutaryl, PPARr: peroxisome proliferator activated receptor, BFC: 7-benzoxy-4-trifluoromethylcoumarin, DBF: dibenzylfluorescein.

catalyzed hydroxylation of atorvastatin had a higherKm and lower Vmax than the CYP3A4-catalyzedhydroxylation of atorvastatin, resulting in a lowerVmax/Km values for CYP3A5. Of interest, theVmax/Km values of vincristine dehydrogenation andKR-63198 hydroxylation by CYP3A5 were morethan 10 times those for CYP3A4.26, 38)

The effects of cytochrome b5 on the metabolicactivities of CYP3A4 and CYP3A5 are summarizedin Table 4.26, 32, 34, 36) For most of the metabolic re-actions, the CYP3A5/CYP3A4 ratios of Km, Vmax,and Vmax/Km values seem to not be markedly influ-enced by the addition of cytochrome b5. For exam-ple, with or without cytochrome b5, the Vmax andVmax/Km values of CYP3A5 for the formation ofa secondary amine (M1) from vincristine were 7–9 and 9–14 times, respectively, those of CYP3A4,while the Km values of CYP3A5 and CYP3A4 werecomparable.26)

The CYP3A5/CYP3A4 ratios of Km, Vmax, andVmax/Km values and metabolic activity were clas-sified into six groups (Fig. 1); 0 (no activity byCYP3A5), less than 0.1 (CYP3A5� CYP3A4), be-

tween 0.1 and 0.5 (CYP3A5 < CYP3A4), between0.5 and 2 (CYP3A5 ≈ CYP3A4), between 2 and 10(CYP3A5 > CYP3A4), and more than 10 (CYP3A5� CYP3A4). At least 120 of 127 metabolic reac-tions investigated (94%) appeared to be catalyzedby both CYP3A4 and CYP3A5. For these metabolicreactions, 36–49% of the Km, Vmax, and Vmax/Kmvalues for the reactions mediated by CYP3A5 werecomparable with those mediated by CYP3A4. Inter-estingly, 14–18% of Vmax and Vmax/Km values forCYP3A5 were more than twice those for CYP3A4.

Fifty-seven of the 73 metabolic reactions forwhich kinetic parameters were available (78%)were hydroxylation or dealkylation reactions. Whenthe hydroxylation or dealkylation reactions wereanalyzed separately, 52% of the dealkylationreactions and 34% of hydroxylation reactionshad CYP3A5/CYP3A4 ratios of Vmax/Km andmetabolic activities of more than 0.5. In particu-lar, 42% of dealkylation reactions and 20% of hy-droxylation reactions had CYP3A5/CYP3A4 ratiosof metabolic activities of more than 0.5. Overall,38% of the hydroxylation reactions had Km values

No. 3 245

Table 3. Comparison of Metabolic Activities Mediated by CYP3A4 and CYP3A5

Substrate Reaction Substrate concentration b5 Ratio ofCYP3A5/

CYP3A4 ofmetabolicactivity

References

Antibiotics, azoleantifungals

Voriconazole 4-Hydroxylation Beyond Km in HLM — 0.18 – 0.23 Murayamaet al. (2007)54)

Voriconazole N-Oxidation Beyond Km in HLM — 0.23 – 0.27 Murayamaet al. (2007)54)

Antibiotics,macrolides

Clarithromycin 14-Hydroxylation Below Km — 0.03 Williams et al.(2002)20)

Clarithromycin N-Demethylation Below Km — 0.08 Williams et al.(2002)20)

Miocamycin 14-Hydroxylation Beyond Kmin CYP3A4 and HLM

— < 0.05 Kasahara et al.(2000)55)

Antimalarials Quinacrine N-Deethylation ? — (1.1) Huang et al.(2006)56)

Anticholinergics Oxybutynin N-Deethylation Below Km in HLM — 1.76 Lukkari et al.(1998)57)

Antivirals and HIVdrugs

Amprenavir N-Dealkylation(M1 formation)

? — 0.73 Tréluyer et al.(2003)58)

Amprenavir Oxidation at alipha-tic chain (M2 for-mation)

Near Km in HLM — 0.74 Tréluyer et al.(2003)58)

Amprenavir Oxidation at tetra-hydrofuran ring(M3 formation)

Near Km in HLM — 0.21 Tréluyer et al.(2003)58)

Amprenavir Oxidation at tetra-hydrofuran ring(M4 formation)

? — 0.33 Tréluyer et al.(2003)58)

Amprenavir Oxidation at ani-line ring (M5 for-mation)

? — 0.08 Tréluyer et al.(2003)58)


N-Demethyltamo-xifen

α-Hydroxylation Beyond Km in HLM — (0.2) Desta et al.(2004)59)

4-Hydroxytamoxi-fen

3-Hydroxylation Beyond Km in HLM — (7.0) Desta et al.(2004)59)

4-Hydroxytamoxi-fen

N-Demethylation(endoxifen forma-tion)

Near Km in HLM — (0.5) Desta et al.(2004)59)

Lonafarnib Hydroxylation atpiperidine ring (M1and M2 formation)

Near Km in HLM — (0.4) Ghosal et al.(2006)60)

Cold and allergyagent

Dextromethorphan N-Demethylation Below Km — 1.07 Huang et al.(2004)13)

Diabetes drug Pioglitazone C-Hydroxylation ? — (0.7) Jaakkola et al.(2006)61)

HMG-CoA reduc-tase inhibitor

Lovastatin 3′′-Hydroxylation Beyond Km in HLM — 0.06 Jacobsen et al.(1999)62)

Lovastatin 6′-Exomethyleneformation

Beyond Km in HLM — 0.08 Jacobsen et al.(1999)62)

Pravastatin 3′′-Hydroxylation Below Km in HLM — 0.13 Jacobsen et al.(1999)62)

Pravastatin 3′α,5′β, 6′β-Hydro-xylation

Below Km in HLM — 0.03 Jacobsen et al.(1999)62)

246 Vol. 56 (2010)



References

Hypnotic agent Indiplon N-Demethylation Below Km inCYP3A4 and HLM

— (0.3) Madan et al.(2007)63)

Prokinetic agent Cisapride N-Dealkylation Below Km inCYP3A4 and HLM

— 0.003 – 0.004 Pearce et al.(2001)64)

Cisapride 3-Fluoro-4-hydroxy cisaprideformation

Below Km inCYP3A4 and HLM

— 0.003 – 0.006 Pearce et al.(2001)64)

Cisapride 4-Fluoro-2-hydroxy cisaprideformation

Below Km inCYP3A4 and HLM

— 0.010 – 0.016 Pearce et al.(2001)64)

Psychotropics,sedative/hypnotics

Buspirone N-Dealkylation Near Km in HLM — < 0.03 Zhu et al.(2005)65)

Buspirone 3′-Hydroxylation Near Km in HLM — < 0.03 Zhu et al.(2005)65)

Buspirone 5-Hydroxylation Below Km in HLM — < 0.03 Zhu et al.(2005)65)

Buspirone 6′-Hydroxylation Near Km in HLM — < 0.03 Zhu et al.(2005)65)

Buspirone N-Oxide formation Below Km in HLM — < 0.03 Zhu et al.(2005)65)

Quetiapine Sulfoxide forma-tion

Below Km — 0.12 Bakken et al.(2009)66)

Quetiapine Sulfoxide forma-tion

Below Km +C 0.12 Bakken et al.(2009)66)

Quetiapine N-Demethylation Below Km — 0.22 Bakken et al.(2009)66)

Quetiapine N-Demethylation Below Km +C 0.22 Bakken et al.(2009)66)

Quetiapine C-Demethylation Below Km — 2.49 Bakken et al.(2009)66)

Quetiapine C-Demethylation Below Km +C 1.39 Bakken et al.(2009)66)

Quetiapine 7-Hydroxylation Below Km — 0.39 Bakken et al.(2009)66)

Quetiapine 7-Hydroxylation Below Km +C 0.38 Bakken et al.(2009)66)

(+)-Risperidone 9-Hydroxylation Near Km in HLM — 0.71 Yasui-Furukoriet al. (2001)67)

(−)-Risperidone 9-Hydroxylation Near Km in HLM — 0.69 Yasui-Furukoriet al. (2001)67)

Statins Simvastatin hydro-xyl acid

3′-Hydroxylation (Near Vmax) — 0.12 Prueksaritanontet al. (2003)68)

Simvastatin hydro-xyl acid

3′,5′-Dihydrodiolformation

(Near Vmax) — 0.10 Prueksaritanontet al. (2003)68)

Simvastatin hydro-xyl acid

6′-Exomethyleneformation

(Near Vmax) — 0.09 Prueksaritanontet al. (2003)68)

Steroid hormones DHEA 7α-Hydroxylation ? — 1.0 Miller et al.(2004)69)

DHEA 7β-Hydroxylation ? — 0.54 Miller et al.(2004)69)

No. 3 247



References

DHEA 16α-Hydroxylation ? — 0.25 Miller et al.(2004)69)

17α-Hydroxypro-gesterone caproate

M2 formation Near Km in HLM — 2.08 Sharma et al.(2008)70)

Miscellaneousagents

1,8-Cineole 2-Exo-hydroxy-lation

Beyond Km inCYP3A4 and HLM

— 0.25 Miyazawa et al.(2001)71)

S -Methyl N,N-diethyldithiocarba-mate

Sulfine formation Below Km in HLM — 0.22 Pike et al.(2001)72)

1α,25-Dihydroxy-vitamin D3

23R-Hydroxylation Near Km in HLM — 0.11 Xu et al.(2006)73)

1α,25-Dihydroxy-vitamin D3

23R-Hydroxylation Near Km in HLM +E 0.04 Xu et al.(2006)73)

Bold: The ratio of the activities of CYP3A5 and CYP3A4 was less than 0.5 times or more than 2 times. The values in parenthesis are estimatedfrom figures in the article. HLM: human liver microsomes, +C: Coexpressed b5, +E: Exogenous b5, DHEA: dehydroepiandrosterone.

Table 4. Effect of Cytochrome b5 on Kinetic Parameters for Metabolic Reactions Catalyzed by CYP3A4 and CYP3A5

Substrate Reaction b5 Ratio (CYP3A5/CYP3A4) ReferenceKm Vmax Vmax /Km

Cancer chemotherapy Vincristine M1 formation (dehydrogenation) — 0.73 9.00 12.39 Dennison et al.(2006)26)+C 0.52 7.38 14.31

+E 0.84 7.24 8.60Immunosuppressants Tacrolimus 13-O-Demethylation — 1.50 2.00 1.67 Dai et al. (2006)32)

+C 1.00 2.13 2.1612-Hydroxylation — 0.45 0.50 1.88 Dai et al. (2006)32)

+C 1.21 2.33 2.00Opioids Alfentanil Piperidine N-dealkylation — 0.76 0.85 1.12 Klees et al. (2005)34)

+E 1.10 1.80 1.60Amide N-dealkylation — 0.78 0.35 0.40 Klees et al. (2005)34)

+E 1.46 0.87 0.57Oxycodone N-demethylation — — — 1.42 CYP3A5 did not

reach apparent sat-uration within thesubstrate concentra-tion used. Lalovic etal. (2004)36)

+E — — 1.25 CYP3A5 did notreach apparent sat-uration within thesubstrate concentra-tion used. Lalovic etal. (2004)36)

Bold: The ratio of the parameters for CYP3A5 and CYP3A4 was less than 0.5 times or more than 2 times. +C: Coexpressed b5, +E: Exogenousb5.

248 Vol. 56 (2010)

Fig. 1. Comparison of the Contributions of CYP3A4 and CYP3A5 to Drug Oxidation RatesRatios for CYP3A5/CYP3A4 were classified in six groups: 0 (�), ≤ 0.1 ( ), 0.1–0.5 ( ), 0.5–2 ( ), 2–10 ( ), and ≥ 10 ( ). a) The reactions

for which the metabolic activity was reported, but not the kinematic parameters, include those catalyzed by CYP3A4 but not by CYP3A5 (see Table 1).

for CYP3A5 that were more than twice those forCYP3A4, whereas the figure for dealkylation reac-tions was 22%.

INHIBITION OF CYP3A4 AND CYP3A5

The observed Ki of CYP3A4 and CYP3A5 aresummarized in Table 5.6, 50, 74, 75) Although inhibi-tion by ketoconazole and diltiazem was investigatedfor the 1′-hydroxylation and 4-hydroxylation of mi-dazolam, there were no marked differences amongthe estimated Ki values between the metabolic re-

actions. For both CYP3A4 and CYP3A5, inhibi-tion by ketoconazole and trans-resveratrol was non-competitive, whereas inhibited by erythromycin,diltiazem, and nicardipine was competitive. Themean/median Ki values for CYP3A5 of the 6 in-hibitors were 5.0± 3.9 (mean± S.D.) and 4.08 (me-dian) times those for CYP3A4. However, theCYP3A5/CYP3A4 ratios of Ki values for azole an-tifungals and calcium channel blockers were morethan 3, whereas the Ki values for CYP3A5 inhibitedby erythromycin and trans-resveratrol were compa-rable with those for CYP3A4.

No. 3 249

Table 5. Inhibition of CYP3A4 and CYP3A5

Inhibitor Substrate Reaction n Type CYP3A5/CYP3A4ratio of Ki

References

Azole Fluconazole Midazolam 1′-Hydroxylation 2 — 8.2 (See below)antifungals 1′-Hydroxylation 1 N 9.19 Gibbs et al.

(1999)74)

1′-Hydroxylation 1 M(CYP3A4)

/CCYP3A5)

7.2 Isoherranen etal. (2008)75)

Ketoconazole Midazolam 1′- or 4-Hydroxylation 3 N 5.5± 2.1 (See below)1′- Hydroxylation 1 N 4.08 Gibbs et al.

(1999)74)

1′-Hydroxylation 1 N 7.88 McConn et al.(2004)6)

4-Hydroxylation 1 N 4.5 McConn et al.(2004)6)

Antibiotics,macrolides

Erythromycin Midazolam 1′-Hydroxylation 1 C 0.9 McConn et al.(2004)6)


trans-Resveratrol BFC Dealkylation 1 N 1.4 Chang and Ye-ung (2001)50)

Calcium channel Diltiazem Midazolam 1′- or 4-Hydroxylation 2 C 3.3 (See below)blockers 1′- Hydroxylation 1 C 3.1 McConn et al.

(2004)6)

4-Hydroxylation 1 C 3.4 McConn et al.(2004)6)

Nicardipine Midazolam 1′-Hydroxylation 1 C 10.8 McConn et al.(2004)6)

(All inhibitors)Mean± S.D.(range)Median

— — — 6 —5.0± 3.9

(0.9 – 10.8)4.4

—

Bold: The ratio of Ki for CYP3A5 and CYP3A4 was less than 0.5 times or more than 2 times. C: competitive inhibition, N: noncompetitiveinhibition, M: mixed-type inhibition, BFC: 7-Benzoxy-4-trifluoromethylcoumarin.

MECHANISM-BASED INHIBITION OFCYP3A4 AND CYP3A5

Mechanism-based inhibition of CYP3A4 bydrugs is due to the chemical modification of theheme, the protein, or both as a result of covalentbinding of modified heme to protein.76) Importantkinetic parameters for mechanism-based inhibition,such as kinact and the apparent Ki, are determinedusing in vitro models.76) Time-dependent inhibi-tion by erythromycin, troleandomycin, saquinavir,raloxifene, tamoxifen, and N-demethyltamoxifenusing midazolam 1′-hydroxylation and/or testos-terone 6β-hydroxylation as the marker reactions,has been observed for CYP3A4 but not for CYP3A5(Table 6);41, 77–79) time-dependent inhibition ofCYP3A5 but not of CYP3A4, however, has not been

reported.The kinact, Ki, and kinact/Ki values for CYP3A4

and CYP3A5 are summarized in Table 7.6, 77, 80)

The kinact and kinact/Ki values of CYP3A5 for the8 inhibitors, other than nelfinavir, were lower thanthose of CYP3A4. The Ki values of CYP3A5 forlopinavir and diltiazem were higher than those ofCYP3A4. Five of the 13 inhibitors investigated(38%) did not exhibit mechanism-based inhibitionof CYP3A5 (Tables 6 and 7).

CONCLUSIONS AND PERSPECTIVES

At least 120 of the 127 metabolic reactions in-vestigated (> 94%) were evidently catalyzed byboth CYP3A4 and CYP3A5, indicating the impor-

250 Vol. 56 (2010)

Table 6. Mechanism-based Inhibitors of CYP3A4 but Not of CYP3A5

Inhibitor Substrate Reaction ReferenceErythromycina) Midazolam 1′-Hydroxylation Soars et al. (2006)41)

Troleandomycin Midazolam 1′-Hydroxylation Soars et al. (2006)41)

Saquinavir Testosterone 6β-Hydroxylation Ernest et al. (2005)77)

Raloxifene Midazolam 1′-Hydroxylation Pearson et al. (2007)78)

Tamoxifen Testosterone 6β-Hydroxylation Zhao et al. (2002)79)

N-Demethyl-tamoxifen Testosterone 6β-Hydroxylation Zhao et al. (2002)79)

a) McConn et al. (2004)6) reported that erythromycin is a mechanism-based inhibitor of CYP3A5.

Table 7. Mechanism-based Inhibitors of both CYP3A4 and CYP3A5

Inhibitor Substrate Reaction CYP3A5/CYP3A4Kinact Ki Kinact /Ki

Erythromycin Midazolam 1′-Hydroxylation 0.26 0.96 0.27 McConn et al. (2004)6)

Amprenavir Testosterone 6β-Hydroxylation 0.48 0.77 0.62 Ernest et al. (2005)77)

Lopinavir Testosterone 6β-Hydroxylation 0.50 2.4 0.20 Ernest et al. (2005)77)

Nelfinavir Testosterone 6β-Hydroxylation 2.1 1.2 1.8 Ernest et al. (2005)77)

Ritonavir Testosterone 6β-Hydroxylation 0.25 1.2 0.21 Ernest et al. (2005)77)

Diltiazem Midazolam 1′-Hydroxylation 0.23 7.1 0.03 McConn et al. (2004)6)

Norverapamil Testosterone 6β-Hydroxylation 0.23 0.44 0.53 Wang et al. (2005)80)

Nicardipine Midazolam 1′-Hydroxylation 0.28 0.66 0.42 McConn et al. (2004)6)

Mean± S.D. 0.54± 0.64 1.8± 2.2 0.51± 0.56Median 0.27 1.08 0.35

Bold: The ratio of the parameters for CYP3A5 and CYP3A4 was less than 0.5 times or more than 2 times.

tance of CYP3A5 in addition to CYP3A4. A newmethod for evaluating the contribution of CYP3A5using metabolic activity classified into six groups(Fig. 1) was introduced in this study. In particu-lar, 14–18% of the Vmax and Vmax/Km values es-timated for CYP3A5 were more than twice thosefor CYP3A4, and the Vmax/Km values of vin-cristine dehydrogenation and KR-63198 hydroxy-lation by CYP3A5 were more than 10 times thosefor CYP3A4.26, 38) These results, shown in Fig. 1,strongly suggest the importance of CYP3A5 inmetabolism in the human liver and intestine, espe-cially in hydroxylation reactions.

The relative contribution of CYP3A5 comparedwith CYP3A4 varies independently of the chemi-cal structure and the reaction positions of the sub-strates. High molecular weight also seems not to bea major factor affecting the CYP3A5/CYP3A4 ra-tios, because the ratios for the kinetic parameters ofcyclosporine A (molecular weight: 1203) were dif-ferent from those of tacrolimus (molecular weight:804). In addition, there were no marked differ-ences in the CYP3A5/CYP3A4 ratios for the kineticparameters between hydroxylation and dealkylationreactions. Bu3) reported that a low Km or Vmax/Kmlipophilicity correlation, but not Vmax lipophilic-

ity correlation, is exhibited for the 215 CYP3A4-mediated reactions of 113 drugs, suggesting a highdegree of difficulty in predicting the kinetic param-eters of CYP3A4 and of CYP3A5 from the chem-ical structure of the substrate. In addition, it hasbeen shown that the experimental conditions, in-cluding the types of CYP3A4/5 expression systemused, affect the relative contributions. Therefore,it is obviously difficult to predict the relative con-tributions of CYP3A5 and CYP3A4 from only thechemical structure and the physicochemical param-eters (e.g., the lipophilicity and acid dissociationconstant (pKa)) of the substrate and/or the reac-tion position. Further studies of molecular structurewith three-dimensional chemical structure analysisof substrates and P450 proteins will be required toenable such prediction in the future.

The Vmax/Km and Vmax values for the dehydro-genation of many dihydropyridine calcium antago-nists, including nifedipine, are lower for CYP3A5than for CYP3A4, whereas the Km values forCYP3A5 are higher than CYP3A4.20, 27–29, 41) In aclinical study it was demonstrated that the CYP3A5genotype did not exert an impact on nifedipinedisposition in healthy volunteers.81) In contrast, itis of interest to note that vincristine is preferen-

No. 3 251

tially metabolized to a secondary amine (M1) byCYP3A5 with a Vmax/Km value 9–14 times thatfor CYP3A4.26) In addition, the estimated hepaticclearances in liver microsomes from CYP3A5 highexpressers are 5 times those from low expressers,suggesting that polymorphic expression of CYP3A5may be a major determinant in the P450-mediatedclearance of vincristine.82) Recently, the importanceof CYP3A5 expression was reportedly confirmed inhuman cryopreserved hepatocytes.83)

For most of the metabolic reactions consideredhere, the CYP3A5/CYP3A4 ratios of Km, Vmax,and Vmax/Km values were not markedly influencedby the addition of cytochrome b5, although an in-crease of the Vmax and/or Vmax/Km values was ob-served (Table 4). On the other hand, the Vmax andVmax/Km values for alprazolam 1′-hydroxylationby CYP3A5 appear to be at least twice thoseby CYP3A4 in the absence of cytochrome b5,40)

whereas the same phenomenon is not observed inthe presence of cytochrome b5.20) In addition, ithas been reported that whether cytochrome b5 isadded by supplementation or coexpression also af-fects the metabolic activity. Ma et al.53) reportedthat the t-butyl hydroxylation and N-demethylationactivities of TPA023 obtained by cytochrome b5-coexpressed CYP3A5 are higher than those of cy-tochrome b5-supplemented CYP3A5. Similarly,CYP3A4 coexpressed with cytochrome b5 resultsin higher catalytic activity toward ifosfamide N-dechloroethylation than that of cytochrome b5-supplemented CYP3A4; this effect was greater thanthat for CYP3A5.25) Also, the Vmax and Vmax/Kmvalues for alfentanil N-dealkylation by cytochromeb5-coexpressed CYP3A4 are higher than thosefor cytochrome b5-supplemented CYP3A4.34) TheVmax/Km of quetiapine with cytochrome b5 wasless than 35% that of CYP3A4, and Vmax/Km forCYP3A4 without cytochrome b5 was 3 times that ofCYP3A4 with coexpressed cytochrome b5, whereasfor CYP3A5, Vmax/Km was similar for both micro-somal preparations.66) Further detailed studies onthe contribution of cytochrome b5 are required inthe future.

The Vmax and Vmax/Km values for manyanti-infective agents, including macrolides (clar-ithromycin and erythromycin) and azole anti-fungals (fluconazole and itraconazole) mediatedby CYP3A5 are lower than those mediated byCYP3A4.12, 13, 20) CYP3A5 with or without cy-tochrome b5 supplementation does not catalyze itra-conazole hydroxylation, and significant metabolism

of itraconazole into metabolic products is not ob-served.12) Similarly, azole antifungal agents, in-cluding ketoconazole and fluconazole, are well-established potent noncompetitive inhibitors ofCYP3A4,2, 74, 84) but the Ki values for CYP3A5 areapproximately 4–9 times those for CYP3A4, al-though they are still in the nanomolar range.2, 6, 74)

In addition, the IC50 values for the inhibition by aza-mulin, fluconazole, and ketoconazole of CYP3A5are reported to be higher than those of CYP3A4.7)

This phenomenon is also observed for macrolideantibiotics (erythromycin and troleandomycin), an-tivirals (amprenavir and indinavir), calcium chan-nel blockers (diltiazem and nicardipine), and an-tidepressants (fluoxetine, fluvoxamine, nafazodone,and trazodone); however, the IC50 values for nel-finavir and ritonavir toward CYP3A5 are lowerthan those toward CYP3A4.7) Erythromycin, dilti-azem, and nicardipine are reported to be competi-tive inhibitors of both CYP3A4 and CYP3A5. Cy-closporine (0.62 µM) causes a 44% decrease of theVmax/Km value of sirolimus depletion by CYP3A4versus only an 8% decrease by CYP3A5.31) Thus,it may be that the inhibition potency is related tothe affinity and/or voracity of the inhibitor towardCYP3A4/5 in the oxidation reaction.

Five of the 13 inhibitors investigated (38%)did not exhibit mechanism-based inhibition ofCYP3A5, and the kinact and kinact/Ki values ofCYP3A5 for 7 of the other 8 inhibitors werelower than those of CYP3A4 (Tables 6 and 7).Mechanism-based inhibition of the metabolism cat-alyzed by CYP3A4 rather than CYP3A5 for dilti-azem has been demonstrated to occur primarily bythe formation of a metabolite intermediate complexwith P450.19)

Some clinical studies have demonstrated thatCYP3A5 is of minimal importance in terms ofthe overall CYP3A metabolic phenotype for someCYP3A substrates, such as midazolam,85–88) alfen-tanil,88) and saquinavir.89) However, the presentinformation suggests the following: the rela-tive contribution of polymorphic CYP3A5 to themetabolism of CYP3A4/5 substrates, especiallyin hydroxylation reactions, is significant, and therisk of adverse drug-drug interactions due to com-petitive and/or mechanism-based inhibition medi-ated by CYP3A5 is lower than that mediated byCYP3A4, although the limitations of this studyshould be considered when interpreting the results.The causal factor(s) and reasons for the differ-ent findings for the kinetic parameters and inhibi-

252 Vol. 56 (2010)

tion constants should be determined in future drugmetabolism and drug interaction studies. In addi-tion, it is suggested that further clinical researchwill be necessary to confirm the contribution ofpolymorphic CYP3A5 relative to that of abundantCYP3A4.

Declaration of interest The authors report no con-flicts of interest. The authors alone are responsiblefor the content and writing of the paper.

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Comparison of the Contributions of Cytochromes P450 3A4 ...jhs.pharm.or.jp/data/56(3)/56_239.pdf · P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those