The Organic Chemistry of Drug Design and Drug Action Chapter 8 Drug Metabolism
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- Slide 1
- 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
- Slide 23
- Heme-dependent Mixed Function Oxidase Scheme 4.35 Oxidizing
agent Reducing agent Activated coenzyme
- Slide 24
- Reactions Catalyzed by Cytochrome P450
- Slide 25
- 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.
- Slide 54
- Allylic Hydroxylation antiarrhythmic Oxidation gives 7.38 (R =
OH)
- Slide 55
- Allylic hydroxylation of THC
- Slide 56
- 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.