The Organic Chemistry of Drug Design and Drug Action Chapter 8
Drug Metabolism
Slide 2
Foreign organism elicits antibody response Low molecular weight
xenobiotics nonspecific enzymes convert them into polar molecules
for excretion Enzymatic biotransformations of drugs drug
metabolism
Slide 3
Principal site of drug metabolism is the liver; also kidneys,
lungs, GI tract take via mouth absorbed through small intestine or
stomach bloodstream liver (first metabolized) Drug metabolism by
liver enzymes first-pass effect Pathway of Oral Drugs
Slide 4
Avoid first-pass effect by changing the route of administration
sublingual route (under the tongue) bypasses liver rectal route
(suppository or enema) intravenous (i.v.) injection rapid response,
circulation time of 15 seconds - angina (sublingual) - migraine
headaches (rectal)
Slide 5
intramuscular (i.m.) injection for large volumes or slow
absorption subcutaneous (s.c.) injection through loose connective
tissue of s.c. layer of skin pulmonary absorption gaseous or highly
volatile drugs topical application Avoid first-pass effect by
changing the route of administration (contd) Prodrug approaches are
discussed in Chapter 9 - asthma (aerosol)
Slide 6
Drug metabolism is desirable once drug has reached site of
action may produce its effect longer than desired or become toxic.
Drug metabolism studies are essential for the safety of drugs.
Metabolites must be isolated and shown to be nontoxic.
Slide 7
An active metabolite that is less toxic Terfenadine is
cardiotoxic, since it binds to the hERG channel Fexofenadine has
similar antihistamine activity, but no hERG activity
Slide 8
Synthesis of Radioactive Compounds To increase sensitivity for
detection of metabolites, radioactivity is incorporated into the
drug candidate. Incorporate a commercial radioactive compound near
the end of the synthesis, if possible. Usually the radioactive
synthesis is different from that of the unlabeled compound. [ 14 C]
preferable to [ 3 H] 3 H has shorter t 1/2 ; isotope effect on C-H
cleavage; loss of 3 H as 3 H 2 O if C-H cleavage occurs Only a
trace amount of radioactivity is used (maybe 1 in 10 6 molecules);
the remainder of the molecules is nonradiolabeled.
Slide 9
Metabolism of erythromycin If the NMe 2 group is labeled with
14 C, the [ 14 C]-CO 2 can be measured.
Slide 10
If the drug is a natural product, a biosynthetic approach to
radioactive incorporation is best SCHEME 8.1 Biosynthesis of
penicillins
Slide 11
If the drug is not a natural product, a chemical synthesis is
needed. [ 14 C] acetic anhydride could be used here SCHEME 8.2
Chemical synthesis of linezolid
Slide 12
The radioactive drug is used in metabolism and bioavailability
studies in rats, mice, or guinea pigs, then in dogs and/or monkeys.
If >95% of the radioactivity is found in urine and feces, and is
nontoxic, it can be administered to humans. Phase I clinical trials
on healthy volunteers radiolabeled drug administered to humans for
human metabolism studies.
Slide 13
Advances that Made Metabolism Studies Less Difficult More
commercially-available radioactive compounds High performance
liquid chromatography (HPLC); new column packings; capillary GC;
capillary electrophoresis New mass spectrometric methods tandem
mass spectrometry/mass spectrometry; GC/mass spectrometry;
*HPLC/electrospray mass spectrometry New nuclear magnetic resonance
(NMR) techniques *HPLC/NMR *HPLC/NMR/MS
Slide 14
Principal Steps in Drug Metabolism Studies 1.Isolation (often,
this step can be omitted) extractions, ion exchange 2.Separations
HPLC, GC 3.Identification mass spectrometry (MS), NMR
4.Quantification radioactive labeling, GC, HPLC LC/MS/MS is a rapid
method in which a sample is injected into the HPLC, then each peak
is run into an electrospray ionization MS for parent ion data, then
the parent ion is run into a second MS for fragmentation data.
Slide 15
Pathways for Drug Deactivation and Elimination Rate and pathway
of drug metabolism are affected by species, strain, sex, age,
hormones, pregnancy, and liver diseases. Drug metabolism is
stereoselective, if not stereospecific. Generally, enantiomers act
as two different xenobiotics different metabolites and
pharmacokinetics. Sometimes the inactive enantiomer produces toxic
metabolites or may inhibit metabolism of active isomer. Metabolism
of enantiomers may depend on the route of administration. For
example, the antiarrhythmia drug verapamil is 16 times more potent
when administered i.v. than orally.
Slide 16
As the lipophilicity increases, metabolism increases; increased
lipophilicity leads to better substrate activity with metabolizing
enzymes. FIGURE 8.1 Effects of lipophilicity on direct renal
clearance and on metabolism
Slide 17
Verapamil is 16 times more active IV than orally The more
active (-) isomer is metabolized faster than the (+) isomer by the
liver
Slide 18
One enantiomer can be metabolized to the other. (Advil)
Inactive (R)-isomer is metabolized to active (S)-isomer No need to
use a single enantiomer
Slide 19
Drug metabolism reactions two categories Phase I
transformations introduce or unmask a functional group, e.g., by
oxygenation or hydrolysis Phase II transformations generate highly
polar derivatives (called conjugates) for excretion
Slide 20
Phase I Transformations Oxidative Reactions Cytochrome P450
family of heme enzymes that catalyzes the same reaction on
different substrates (isozymes) Late 1940s, early 1950s Metabolism
of 4-dimethylaminoazobenzene shown to require O 2 and a reducing
system (NADPH). Called a mixed function oxidase. One atom of O from
O 2 is incorporated into product; a heme protein is involved.
Slide 21
Drug-Drug Interactions Changes in the pharmacokinetics and
metabolism of drugs when multiple drugs are taken together. One
drug may inhibit a cytochrome P450, blocking metabolism of another
drug. One drug may induce a cytochrome P450, which increases
metabolism of other drugs.
Slide 22
Hyperforin is found in St. Johns Wort Active constituent of St.
Johns wort (hyperforin, 8.11) activates the pregnane X receptor,
which regulates P450 3A4 transcription, resulting in more active
drug metabolism
Site of Reactions Catalyzed by P450 Part of molecule undergoing
reaction is determined by: 1.topography of the active site of the
isozyme 2.degree of steric hindrance of the heme iron-oxo species
to the site of reaction 3.ease of H atom abstraction or electron
transfer from the compound
Slide 26
CYP450 activity is variable in the population CYP450 is found
in liver, kidney and lungs. There are a number of different P450
families, which differ in their substrate and reaction specificity.
57 human genes for P450 have been indentified. Individuals also
vary in the properties of their P450s. CYP450 2C9 and 2D6 are
responsible for metabolism of about half of all drugs. Variations
in P450s are racially and ethnically distributed.
Pharmacogenomicshow the genetic characteristics of a person
influences their response to drugs.
Slide 27
Individual variation in CYP450 2C9 CYP450 2C9 metabolizes
phenytoin, S-warfarin, tolbutamide, losartan, and many nonsteroidal
antiinflammatory agents (NSAIDs). At least 33 alleles of CYP450 2C9
have been discovered. Most of the mutant alleles of CYP450 2C9 have
low or no enzymatic activity.
Slide 28
CYP450 2C9 and tolbutamide metabolism Tolbutamide is a
sulfonylurea antidiabetes drug. CYP450 2D9 hydroxylates the
aromatic methyl to give a much lower activity metabolite.
Individuals with mutant CYP450 2C9 alleles have higher
concentrations of tolbutamide in the blood, longer duration of
action, and lower blood glucose, so they are more likely to get
hypoglycemia.
Slide 29
CYP450 2C9 and warfarin metabolism Warfarin is an anticoagulant
drug which inhibits vitamin K 2,3-epoxide reductase. (S)-Warfarin
is hydroxylated at C-6 and C-7 by CYP450 2C9 to give inactive
metabolites. Mutant alleles of CYP450 2C9 have less activity for
hydroxylation of warfarin, so patients with mutant alleles need to
have lower doses. The therapeutic index for warfarin is small even
for wild-type patients.
Slide 30
Individual variation in CYP450 2D6 P450 2D6 metabolizes
opiates, antiarrhytmics, tamoxifen and -blockers, among others.
More than 60 alleles of 2D6 have been discovered. Some of the
alleles of 2D6 have low or no enzymatic activity (PM). Some of the
alleles of 2D6 have intermediate activity (IM). Some of the alleles
of 2D6 have somewhat higher activity (EM). Some of the alleles of
2D6 have much higher activity than wild-type (UM).
Slide 31
CYP450 2D6 and opiate metabolism Codeine is O-demethylated to
morphine, the active metabolite in analgesia. PMs cant convert
codeine to morphine, so dont get analgesia. UMs convert codeine to
morphine very rapidly, so may experience toxicity. Infants have
been poisoned by breast milk from UM mothers taking codeine.
Slide 32
CYP450 2D6 and tamoxifen metabolism Tamixofen is an
antiestrogen used to treat breast cancer. The metabolite,
4-hydroxytamoxifen, binds about 100-fold more strongly to estrogen
receptors. 2D6 PMs respond poorly to tamoxifen treatment.
Slide 33
Reactions of Flavin Monooxygenase Table 8.2 Flavin
monooxygenase is often more stereoselective than CyP450 CyP450
FMO
Slide 34
Flavin Monooxygenase (another mixed function oxidase) Scheme
4.34 X is N or S Nucleophiles with anionic groups are not
substrates
Slide 35
Aromatic Hydroxylation Jerina, Daly and Witkop 1968 National
Institutes of Health (NIH) arene oxide isolated Intermediate in
aromatic hydroxylation SCHEME 8.3 Cytochrome P450 oxidation of
naphthalene
Slide 36
Mechanism for Arene Oxide Formation and Aromatic Hydroxylation
(favored over a) SCHEME 8.4 Additionrearrangement mechanism for
arene oxide formation
Slide 37
Reactions of Arene Oxides toxic effects SCHEME 8.5 Possible
fates of arene oxides
Slide 38
Rearrangement of Arene Oxide to Arenol Called the NIH shift
SCHEME 8.6 Rearrangement of arene oxides to arenols (NIH
shift)
Slide 39
Competing with the NIH Shift deprotonation The more stabilized
the carbocation intermediate, the less favored for hydride shift -
more deprotonation. SCHEME 8.7 Competing pathway for NIH shift
Slide 40
Deuteration can reduce metabolism Deuterated linezolid has t
1/2 = 6.3 h, compared to 4.5 h
Slide 41
NIH Shift with Groups Other than H p-chloroamphetamine
Oxidation of a halogen-substituted aromatic ring is quite rare.
SCHEME 8.8 NIH shift of chloride ion
Slide 42
A common approach to slow down or block aromatic hydroxylation
is to substitute the phenyl ring with a para-fluorine or
para-chlorine (deactivates the ring). The half-life for the
anti-inflammatory drug diclofenac (8.22) is 1 h; for fenclofenac
(8.23) is >20 h.
Slide 43
NIH Shift of a Nitro Group Scheme 8.9 antiprotozoal
Slide 44
This reaction is electrophilic aromatic substitution Favors
electron-donating substituents No aromatic hydroxylation if
strongly electron-withdrawing substituents e - withdrawing
uricosuric agent
Slide 45
For drugs with 2 aromatic rings, the more e - -rich one usually
is hydroxylated. hydroxylation here e - withdrawing -
antipsychotic
Slide 46
Species Specificity Major hydroxylation metabolites in dogs
Maybe a different isozyme pro-R - antiepilepsy pro-S in humans
Slide 47
Mechanism of Epoxide Hydrolase Hydration of Arene Oxide
trans-diol anti- attack SCHEME 8.10 Metabolic formation and
oxidation of catechols
Slide 48
Glutathione S-transferase Reaction with Arene Oxide SCHEME 8.11
Formation of glutathione adducts from naphthalene oxides
Slide 49
Toxicity from Arene Oxides benzo[a]pyrene alkylation of DNA and
RNA Relationship between soot and cancer noted in 1775 - chimney
sweeps frequently developed skin cancer SCHEME 8.12
Deoxyribonucleic acid adduct with benzo[a]pyrene metabolite
Slide 50
Alkene Epoxidation Also an anticonvulsant anticonvulsant SCHEME
8.13 Metabolism of carbamazepine
Slide 51
Toxic Product of Alkene Oxygenation aflatoxin B 1 DNA adduct
SCHEME 8.14 Metabolic reactions of aflatoxin B 1
Slide 52
Oxidation of Carbons Adjacent to sp 2 Centers Oxygenation next
to aromatic sp 2 carbon antidepressant
Slide 53
Hydroxylation stereochemistry at C-1 depends on stereochemistry
at C-2 in metoprolol. antihypertensive Stereochemistry at C-2 will
affect how the molecule binds in P450, which determines which H is
closest to the heme iron-oxo species.
Oxidation Next to a Carbonyl Group Enantiomer difference in
metabolism hydroxylation here for (+)-isomer hydroxylation here for
(-)-isomer sedative/hypnotic
Slide 57
Oxidation at Aliphatic and Alicyclic Carbons anticonvulsant
Both positions are hydroxylated
Slide 58
Perhexiline is hydroxylated
Slide 59
Hydroxylation beta to a Carbonyl Group SCHEME 8.15
C-demethylation of a flutamide metabolite
Slide 60
Oxidations of Carbon-Nitrogen Systems
Slide 61
Oxidative Deamination Cleavage of NH 3 from 1 amines SCHEME
8.16 Oxidative deamination of primary amines
Slide 62
Oxidative Deamination of amphetamine
Slide 63
SCHEME 8.17 N-Oxidation pathways of amphetamine
N-Oxidation-Hydroxylation of Nitrogen Basic amines (pK a 8-11) are
oxidized by flavoenzymes. Nonbasic compounds, such as amides, are
oxidized by P450. Compounds of intermediate basicity, such as
aromatic amides, are oxidized by both.
Slide 64
Alternative Pathway to Ketone SCHEME 8.18 Amphetamine imine
formation via the carbinolamine
Slide 65
Metabolism of 2 Amines and Amides
Slide 66
Oxidative N-Dealkylation SCHEME 8.19 Oxidative N-dealkylation
of secondary amines
Slide 67
Oxidation here ab SCHEME 8.20 Oxidative metabolism of
propranolol
Slide 68
N-Oxidation of 2 Amines anorectic Further oxidation occurs
SCHEME 8.21 N-Oxidation of fenfluramine
Slide 69
Oxidation of 3 Amines and Amides No oxidative deamination
Slide 70
Oxidative N-Dealkylation Rate of oxidative N-dealkylation of 3
amines > oxidative N-dealkylation of 2 amines > oxidative
deamination of 1 amines antihypertensive drug Rate of metabolism R
= NMe 2 > NHMe > NH 2 antidepressant drug
Slide 71
Enantioselective Oxidative N-Dealkylation N-Demethylation of
(+)-isomer is slower than that of (-)-isomer narcotic
analgesic
Slide 72
(S)-(+)-deprenyl (S)-(+)-methamphetamine (S)-(+)-amphetamine
weak MAO B inhibitor undesirable CNS stimulant (R)-(-)-deprenyl
(R)-(-)-methamphetamine (R)-(-)-amphetamine potent MAO B inhibitor
weak CNS stimulant Therefore only the (R)-(-)-isomer is used SCHEME
8.22 Metabolism of selegiline (deprenyl)
Slide 73
Rasagiline avoids the stimulation problem with Seligiline
Slide 74
Alicyclic 3 Amine Oxidation SCHEME 8.23 Oxidative metabolism of
nicotine leading to CN bond cleavage.
Slide 75
Evidence for Iminium Ion Intermediates local anesthetic
isolated SCHEME 8.24 Metabolism of lidocaine
Slide 76
N-Oxidation of 3 Amines N-Oxidation antihypertensive
Slide 77
Cyproheptadine forms the N- oxide in dogs
Slide 78
N-Oxidation of 3 Aromatic Amines Two enzymes systems: P450 and
flavin monooxygenase P450 catalyzed N-oxidation N-Oxidation by P450
occurs only if there are no -hydrogens available or if the iminium
radical is stabilized by electron donation. SCHEME 8.25 Mechanism
of cytochrome P450-catalyzed N-oxidation of tertiary aromatic
amines
Slide 79
Flavin Monooxygenase-Catalyzed N-Oxidation of Aromatic Amines
Primary aromatic amines are generally not substrates for flavin
monooxygenase; 2 and 3 aromatic amines are good substrates. SCHEME
8.26 Possible mechanism for N-oxidation of primary arylamines
Slide 80
Two Pathways for N-Demethylation of 3 Aromatic Amines SCHEME
8.27 Two pathways to N-demethylation of tertiary aromatic
amines
Slide 81
Evidence to Support Carbinolamine Formation R = OH
isolated
Slide 82
Mechanism of Carbinolamine Formation Based on low intrinsic
isotope effects by P450, direct H abstraction mechanism was
excluded. SCHEME 8.28 Mechanism of carbinolamine formation during
oxidation of tertiary aromatic amines
Slide 83
N-Oxidation of Aromatic Amines (1 and 2 ) Generation of
reactive electrophiles acetylation or sulfation SCHEME 8.29
Metabolic activation of primary and secondary aromatic amines
Slide 84
Cytotoxicity of N-Hydroxylated Amides Mechanism-based
inactivator if 8.78 does not escape the enzyme prior to
nucleophilic attack SCHEME 8.30 Arylhydroxamic acid
N,O-acyltransferase-catalyzed activation of
N-hydroxy-2-acetylaminoarenes
Slide 85
Amide N-Demethylation sedative
Slide 86
N-Oxidation of 1 and 2 Aromatic Amides Generation of
electrophiles 2-acetylaminofluorene (R = H) carcinogenic agent
Slide 87
SCHEME 8.31 Initial proposals for bioactivation of
acetaminophen Toxicity of Acetaminophen Two possible mechanisms for
generation of reactive electrophile 8.80
Slide 88
Another possible mechanism for Acetaminophen Hepatotoxicity
Ethanol induces a P450 isozyme that generates the radical;
alcoholics have a higher incidence of acetaminophen hepatotoxicity.
SCHEME 8.32 Bioactivation of acetaminophen via a radical
intermediate
Slide 89
Prostaglandin H synthase is in high concentrations in kidneys.
Prostaglandin H synthase contains heme just like P450 and catalyzes
similar reactions Acetaminophen also causes renal damage, but
little P450 is in the kidneys. SCHEME 8.33 Proposed bioactivation
of acetaminophen by prostaglandin H synthase
Slide 90
Oxidations of Carbon-Oxygen Systems Oxidative O-Dealkylation
Same mechanism as oxidative N-dealkylation O-Demethylation is
rapid; as increase alkyl chain length, O-dealkylation gets faster
up to propoxyl, then rate decreases. Cyclopropyl gives ethers with
longer plasma half lives.
Slide 91
Indomethacin is demethylated
Slide 92
Oxidative O-Dealkylation of codeine analgesic O-Demethylation
by Cyp450 2D6 is rapid
Slide 93
Regioselective O-Demethylation In dogs O-demethylation only
here blood pressure maintenance
Slide 94
Oxidation on the Carbon Next to a Lactone Oxygen SCHEME 8.34
Metabolic hydroxylation of rofecoxib
Slide 95
Oxidations of Carbon-Sulfur Systems Three principal
biotransformations: Oxidative S-dealkylation, desulfuration, and
S-oxidation Oxidative S-dealkylation sedative Dealkylation occurs
here
Slide 96
Desulfuration (C=S C=O) anesthetic sedative
Slide 97
S-Oxidation Occurs with P450 and flavin monooxygenase Flavin
monooxygenase gives sulfoxides only P450 gives both S-dealkylation
and sulfoxides SCHEME 8.35 Cytochrome P450-catalyzed oxidation of
sulfides
Slide 98
antihelmintic agent Gives both S-dealkylation and S-oxidation
metabolites
Slide 99
Thioridazine is oxidized on both sulfurs
Slide 100
Thiophenes are converted to thiophene S-oxides, which are
electrophilic and can bind to liver proteins. added in vitro to
mimic a liver protein cysteine residue SCHEME 8.36 S-Oxidation of
tienilic acid
Slide 101
Oxidation of Sulfoxide to Sulfone Oxisuran, an immunosupressive
drug, is oxidized to the sulfone
Slide 102
Other Oxidative Reactions Oxidative Dehalogenation volatile
anesthetic SCHEME 8.37 Oxidative dehalogenation of halothane
Slide 103
Oxidative Aromatization
Slide 104
Oxidation products of morphine
Slide 105
Oxidation of Alcohols to Aldehydes and Aldehydes to Carboxylic
Acids Scheme 8.38 Oxidation of an aldehyde to a carboxylic acid is
generally faster than reduction of an aldehyde to an alcohol.
Cytochrome P450 also oxidizes alcohols to aldehydes and aldehydes
to carboxylic acids.
Slide 106
Oxidation of an Alcohol to a Carboxylic Acid by NAD + Enzymes
anti-AIDS drug
Slide 107
Oxidation of an Alcohol to a Carboxylic Acid by a P450 Isozyme
The metabolite is 10 times more potent an antagonist of the
angiotensin II receptor than losartan. antihypertensive drug
Slide 108
Reductive Reactions
Slide 109
Carbonyl Reduction Typically aldo-keto reductases that require
NADPH or NADH and 7-hydroxyl) as the major metabolites.
Administration of racemates can affect the metabolism of each
enantiomer. When the racemic mixture was administered, the R-isomer
gave aromatic hydroxylation (both 6- Reduced here Hydroxylated here
(R)-isomer: (R,S) alcohol (S)-isomer: R=OH + 4:1 (S,S) : (S,R)
alcohols
Slide 110
Species Variation in Stereochemistry opioid antagonist used for
addiction rehabilitation 6 -alcohol (7.102, R 1 = OH, R 2 = H) in
chickens 6 -alcohol (7.102, R 1 = H, R 2 = OH) in rabbits and
humans
Slide 111
, -Unsaturated Ketone Double Bonds Reduced The double bond of
norgestrel (7.94, R 3 = Et) and norethindrone (7.94, R 3 = Me) is
reduced; norgestrel gives 3 -alcohol (R 1 = H, R 2 = OH) but
norethindrone gives 3 -alcohol (R 1 = OH, R 2 = H). Double bond
reduced
Slide 112
Nitro Reduction SCHEME 8.39 Nitro group reduction
Slide 113
Nitro Reduction Often the amine metabolite is not observed
because it is easily air oxidized back to the nitro compound, for
example, the anti-parasitic agent niridazole is reduced to the
hydroxylamine, but is reoxidized to niridazole, and clonazepam is
reduced to the unstable amine.
Slide 114
Nitro reduction with ring opening SCHEME 8.40 Reductive
metabolism of nitrofurazone
Slide 115
Azo Reduction SCHEME 8.41 Azo group reduction
Slide 116
Azo Reduction Reduction carried out by intestinal bacteria.
SCHEME 8.42 Reductive metabolism of sulfasalazine
Slide 117
Reduction of Azido to Amino Anti-AIDS
Slide 118
3 Amine Oxide Reduction imipramine N-oxide Reduced in the
presence of O 2 to the amine
Slide 119
Reductive Dehalogenation Cytochrome P450 in the absence of O 2
May be the cause for Halothane hepatitis SCHEME 8.43 Reductive
dehalogenation of halothane
Slide 120
Carboxylation Reactions Metabolized to 8.124, R = COOH
Slide 121
Hydrolytic Reactions (nonspecific esterases and amidases in
plasma, liver, kidney, and intestines) Electron-withdrawing groups
accelerate hydrolysis. Conjugation with carbonyls decelerates
hydrolysis. Steric hindrance decelerates hydrolysis. Hydrolyzed by
all human tissues
Slide 122
Selectivity for Aliphatic vs. Aromatic Esters Some esterases
catalyze the hydrolysis of aliphatic esters and others aromatic
esters. In vivo hydrolysis Hydrolysis by liver enzymes in
vitro
Slide 123
Amide vs. Ester Hydrolysis Hydrolysis of procaine >>
procainamide Generally amides are more slowly hydrolyzed than
esters.
Slide 124
Amide vs. Ester Hydrolysis No amide hydrolysis Ester hydrolysis
only
Slide 125
Some amides are hydrolyzed at rates comparable to that of
esters (maybe because of electron- withdrawing groups).
Slide 126
Hydrolysis of phenacetin produces a toxic amine
Slide 127
Amide Hydrolysis - Enantiomer Toxicity Both enantiomers are
anesthetics (R)-isomer causes methemoglobinemia (S)-isomer not
hydrolyzed
Slide 128
Stereospecific metabolism of phensuximide, an
anticonvulsant
Slide 129
Enantiomer-Selective Hydrolysis The (R)-(-)-ester is hydrolyzed
in the liver, but the (S)-(+)-ester is hydrolyzed in the
brain.
Slide 130
Differential Enantiomeric Metabolism SCHEME 8.44 Competitive
metabolism of R- and S-etomidate (R)-enantiomer (S)-enantiomer
Slide 131
Phase II Transformations Conjugation Reactions Attachment of
small polar endogenous molecules to drugs or (more often) to
metabolites of phase I enzymes Further deactivates drugs and
produces water- soluble metabolites readily excreted Conjugation
reactions take place with hydroxyl, carboxyl, amino, heterocyclic
N, and thiol groups; if not present, a phase I reaction introduces
it Many drugs are excreted without any modification at all.
Slide 132
Mammalian Phase II Transformations Table 8.7
Slide 133
Glucuronidation Biosynthesis and Reactions of UDP-glucuronic
Acid SCHEME 8.45 Biosynthesis and reactions of UDP glucuronic
acid
Slide 134
Classes of Compounds Forming Glucuronides
Slide 135
Diseases (inborn errors of metabolism) associated with
defective glucuronidation Crigler-Najjar syndrome and Gilberts
disease deficiency of UDP-glucuronosyltransferase adverse effects
caused by accumulation of drugs inability of neonates to conjugate
the antibacterial chloramphenicol (8.142) - gray baby
syndrome)
Slide 136
Species Specificity, Regioselectivity, and Stereoselectivity
Antibacterial drug sulfadimethoxine is glucuronidated in humans (at
arrow) but not in rats, guinea pigs, or rabbits.
Sulfadimethoxine
Slide 137
Two different glucuronides are formed here The R,R-(-)-isomer
is conjugated with higher affinity, but lower velocity than is the
S,S-(+)- isomer.
Slide 138
The two hydroxylated isomers of nortriptyline metabolite 8.144
(R = OH) are glucuronidated stereospecifically. Liver and kidney
glucuronosyltransferases convert only the E-(+)- isomer and the
intestinal enzyme converts only the (E)-(-)- isomer.
Slide 139
Human UGTs 40-70% of drugs are glucuronidated in humans.
Twenty-two UGTs have been identified.
Slide 140
Polymorphisms of UGT1A1
Slide 141
Polymorphisms of UGT1A3
Slide 142
UGT alleles can lead to severe side effects
Slide 143
Sulfate Conjugation Occurs less often than glucuronidation
(limited availability of SO 4 = ). Main substrates are phenols, but
also aliphatic OH, amines, and thiols (much less).
Slide 144
Glucuronidation and sulfation can occur on the same substrates,
but the K m for sulfation is usually lower, so it predominates.
bronchodilator sulfation here (phenolic OH instead of aliphatic
OH)
Slide 145
Hepatotoxicity and Carcinogenicity by Sulfation SCHEME 8.47
Bioactivation of phenacetin
Slide 146
Amino Acid Conjugation Glycine conjugates are most common in
animals. L-Glutamine conjugates are most common in primates
(insignificant in nonprimates). SCHEME 8.48 Amino acid
conjugation
Slide 147
Metabolism of Brompheniramine (antihistamine) SCHEME 8.49
Metabolism of brompheniramine
Slide 148
Metabolism of diphenhydramine (Benadryl) The pathway is the
same as bromopheniramine, except that it is conjugated with
glutamine
Slide 149
Glutathione Conjugation Glutathione GSH Found in all mammalian
tissues (5-10 mM in liver and kidneys) Scavenger of harmful
electrophiles
Slide 150
Glutathione Conjugation SCHEME 8.50 Examples of glutathione
conjugation
Slide 151
Further Metabolism of GSH Conjugates Metabolism of glutathione
conjugates to N-acetyl- L-cysteine conjugates Referred to as phase
III metabolism SCHEME 8.51 Metabolism of glutathione conjugates to
mercapturic acid conjugates
Slide 152
Water Conjugation Epoxide hydrolase reactions; such as
hydrolysis of arene oxides, as discussed earlier.
Slide 153
Acetyl Conjugation Important for xenobiotics with primary NH 2
Converts ionized amine (RNH 3 ) to uncharged amide + Metabolites
are less water soluble; possibly serves the function of
deactivating the drug. Occurs widely in animals Extent of
N-acetylation in humans is a genetically determined characteristic
- called acetylation polymorphism. Egyptians are slow acetylators -
toxic buildup of drugs but longer drug effectiveness. East Asians
and Canadian Eskimos are fast acetylators - inadequate
response.
Slide 154
Acetylation of Amines Makes less polar: RNH 3 + SCHEME 8.52
N-Acetylation of amines
Slide 155
Examples of Drugs Exhibiting Acetylation Polymorphism
Antibacterial Antituberculosis Treatment of leprosy
Slide 156
Cilastatin is acetylated. It is administered with Imipenem
Slide 157
Fatty Acid and Cholesterol Conjugation Fatty acid metabolites
of 8.177 and 8.178 deposit in liver, spleen, adipose tissue, and
bone marrow.
Slide 158
Cholesterol esters can be formed Development of the
hypolipidemic drug 8.180 had to be stopped because cholesterol
esters deposited in the liver.
Slide 159
Methylation - relatively minor in drug metabolism Generally
occurs when the compound has a structural similarity to normal
endogenous substrates of the methyltransferase. SCHEME 8.53
Methylation of xenobiotics
Slide 160
Methylated here regiospecifically bronchodilator Methylation by
catechol O- methyltransferase requires a catechol (an aromatic 1,2-
dihydroxy) substrate. An aromatic 1,3-dihydroxy compound (8.185)
does not get methylated.
Slide 161
Phenolic hydroxyls also can get methylated Methylation here
(minor)
Slide 162
N-Methylation also occurs to a minor extent. Oxyprenolol is
N-dealkylated to 8.187, R = H, which is methylated to 8.187, R = CH
3. antihypertensive
Slide 163
Captopril and propylthiouracil are S-methylated.
S-Methylation
Slide 164
Reactive metabolites Atorvastatin and lumiracoxib can form an
electrophilic quinone imine.
Slide 165
Hard and Soft Drugs Sometimes a drug is not metabolized rapidly
enough (long plasma half life). The plasma half life for an analog
(8.196) of the antiarthritis drug celecoxib (8.195) in dogs is
about a month! To shorten the plasma half life the para-chloro was
changed to para-methyl because a carbon next to an aromatic group
is known to undergo P450 oxygenation. plasma t 1/2 9 hplasma t 1/2
680 h
Slide 166
Compounds (like 8.196) that are difficult to metabolize are
termed hard drugs. Those that are easily metabolized (like 8.195)
are soft drugs (also called antedrugs). Soft drugs are designed to
have a predictable and controllable metabolism to nontoxic and
inactive products after they have achieved their pharmacological
effect.
Slide 167
8.197 is a soft analogue of 8.198, an antifungal
Slide 168
Retro Approach Related to Soft Drugs Identify a biologically
inactive metabolite, then modify to an active drug in such a way
that this modification is known to be reversed to the inactive
metabolite. The anti-inflammatory agent loteprednol etabonate
(8.199) was designed based on the known inactive steroid 8.201 [an
analog of the anti- inflammatory drug prednisolone (8.200)].
Compound 8.199 is metabolized by esterases to 8.201 after it
elicits its anti- inflammatory effect.