Drug metabolism

DRUG METABOLISM www.freelivedoctor.com

Transformation of Xenobiotics by Biological Systems www.freelivedoctor.com

IMPLICATIONS FOR DRUG METABOLISM www.freelivedoctor.com

IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis www.freelivedoctor.com

Termination of Drug Action www.freelivedoctor.com tropic acid and tropine atropine propranolol  hydroxypropranolol (active) (active)

Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite www.freelivedoctor.com

Activation of Prodrug www.freelivedoctor.com Dopamine L-dopa

Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine terfenadine fexofenadine activation of prodrug www.freelivedoctor.com

Some Xenobiotics Are Metabolized to Carcinogenic Agents
3,4 Benzopyrene
Aflatoxin
N-Acetylaminoflluorene
Metabolites of these agents interact with DNA carcinogenesis www.freelivedoctor.com

Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine Bioactivation of acetaminophen; under certain conditions, the electrophile N-acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. bioactivation www.freelivedoctor.com

Thalidomide is a Teratogen
THALIDOMIDE: Fetal malformations in humans, monkeys, and rats occur due to metabolism of the parent compound to a teratogen. This occurs very early in gestation.
teratogensis www.freelivedoctor.com

FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com

Factors Affecting Drug Metabolism
Age
Diet
Genetic Variation
State of Health
Gender
Degree of Protein Binding
Species Variation
Substrate Competition
Enzyme Induction
Route of Drug Administration
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Route of drug administration
Oral versus systemic administration

Many Drugs Undergo First Pass Metabolism Upon Oral Administration
Oral administration
Drug travels from gut to portal vein to liver
Vigorous metabolism occurs in the liver. Little drug gets to the systemic circulation
The wall of the small intestine also contributes to first pass metabolism

ORGAN SITES OF DRUG METABOLISM www.freelivedoctor.com

Organ Sites of Drug Metabolism
Liver
Small intestine
Kidney
Skin
Lungs
Plasma
All organs of the body

CELLULAR SITES OF DRUG METABOLISM www.freelivedoctor.com

Cellular Sites Of Drug Metabolism
Cytosol
Mitochondria
Lysosomes
Smooth endoplasmic reticulum (microsomes)

KINETICS OF DRUG METABOLISM www.freelivedoctor.com

Velocity Of Metabolism Of A Drug D:summer1Kmx1.pzm www.freelivedoctor.com

Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com

First Order Metabolism v = Vmax [C] Km + [C] When Km >>> [C], then v = Vmax [C] , Km and v  [C] Metabolism of the drug is a first order process. A constant fraction of the remaining drug is metabolized per unit time. Most drugs are given at concentrations smaller than the Km of the enzymes of their metabolism. A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug. www.freelivedoctor.com

Zero Order Metabolism v = Vmax [C] K m + [C] When [C] >>> Km, then v = Vmax [C] , [C] and v = Vmax Metabolism of the drug is a zero order process. A constant amount of the remaining drug is metabolized per unit time. Phenytoin undergoes zero order metabolism at the doses given. A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug. www.freelivedoctor.com

Velocity Of Metabolism Of Three Drugs By The Same Enzyme www.freelivedoctor.com

PHASES OF DRUG METABOLISM www.freelivedoctor.com

Phase I Metabolism R R OH R R COOH R R SH R R NH 2 Polar groups are exposed on or introduced to a molecule www.freelivedoctor.com

Phase I Reactions OXIDATION REDUCTION HYDROLYSIS www.freelivedoctor.com

Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com D+ ENDO X D X + ENDO

Patterns of Drug Metabolism
Parent molecule  Phase 1 metabolism
Phase 1 metabolite  Phase 2 metabolism
Parent molecule  Phase 2 metabolism
Phase 2 metabolite  Phase 1 metabolism
Some drugs are not metabolized, for example, gallamine and decamethonium. Atracurium undergoes spontaneous hydrolysis. www.freelivedoctor.com

PHASE I METABOLIC PATHWAYS www.freelivedoctor.com

Microsomal Oxidation www.freelivedoctor.com

Preparation Of Microsomes www.freelivedoctor.com

Cytochrome P450 fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase www.freelivedoctor.com

Oxidation Of Drugs By Cytochrome P450 www.freelivedoctor.com

Aliphatic Oxidation www.freelivedoctor.com

Aromatic Hydroxylation (1) acetanilid p -hydroxyacetanilid www.freelivedoctor.com

Aromatic Hydroxylation (2) www.freelivedoctor.com

N-Dealkylation www.freelivedoctor.com

O-Dealkylation www.freelivedoctor.com

S-Demethylation www.freelivedoctor.com

Oxidative Deamination www.freelivedoctor.com

S-Oxidation www.freelivedoctor.com

N-Oxidation www.freelivedoctor.com

N-Hydroxylation www.freelivedoctor.com

N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com

Oxidative Dehalogenation www.freelivedoctor.com

Desulfuration www.freelivedoctor.com

ISOENZMYES OF CYTOCHROME P450 CYP1A1 CYP1A2 CYP2A6 CYP2B_ CYP2C9 CYP2C19 CYP2D6 CYP2AE1 CYP3A4 CYP3A5 CYP3A7 CYP4A_ www.freelivedoctor.com

Cytochrome P450 3A4 (CYP3A4) www.freelivedoctor.com

CYP3A4
CYP3A4 is responsible for metabolism of 60% of all drugs
It comprises approximately 28% of hepatic cytochrome P450
Metabolizes terfenadine
Ingestion of grapefruit juice reduces expression of this enzyme
Inhibited by some regularly used drugs

Some Drugs That Inhibit CYP3A4
Macrolide antibiotics
Erythromycin
Clarithromycin
Other such agents
Antifungal agents
Ketoconazole
Itraconazole
Other such agents
HIV protease inhibitors

CYP3A4
Ketoconazole and terfenadine can produce a drug interaction with fatal consequences.

CONVERSION OF TERFENADINE TO FEXOFENADINE CYP3A4 O 2, NADPH www.freelivedoctor.com

AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4 www.freelivedoctor.com

Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression J.Clin. Invest. 99:10, p.2545-53, 1997 Hours www.freelivedoctor.com

6',7', - Dihydroxybergamottin www.freelivedoctor.com

Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine www.freelivedoctor.com X

CYP3A4 And P-Glycoprotein
P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs
P-Glycoprotein and CYP3A4 share many substrates and inhibitors

CYP2D6 is an Enzyme with Polymorphisms
Approximately 70 nucleotide polymorphisms are known
Four phenotype subpopulations of metabolizers *
Poor metabolizers (PM)
Intermediate metabolizers (IM)
Extensive metabolizers (EM)
Ultrarapid metabolizers (UM)
Variations according to racial background
More than 65 commonly used drugs are substrates
Codeine is a well known substrate
* The Pharmacological Basis of Therapeutics www.freelivedoctor.com

Codeine is a Substrate of CYP2D6 Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals -CH 3 (methyl morphine) www.freelivedoctor.com

CYP2C9
Metabolizes some 16 commonly used drugs
Warfarin and phenytoin are among the substrates
Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme
Warfarin clearance is greatly reduced in individuals possessing the allelic variants
Dose adjustments are required for drugs in individuals who have the mutant enzymes

CYP2C 19
S-mephenytoin is a substrate
(4-hydroxylation at the phenyl ring )
As much as eight allelic variants identified
All are nonfunctional proteins
Poor metabolizers of S-mephenytoin lack 4-hydroxylase activity, but N-demethylation to nirvanol is an alternative but slow metabolic pathway
Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme

CYP1A1
Polycyclic hydrocarbons are among its substrates
Inducers include
Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc.
Charcoal broiled foods (polycyclic hydrocarbons)

CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs Warfarin Phenytoin Metoprolol Labetalol Quinidine Caffeine Lidocaine Theophylline Alprazolam Diazepam Flurazepam Triazolam Chlordiazepoxide Carbamazepine Quinidine Ethanol Tricyclic antidepressants Metronidazole Calcium channel blockers Diazepam Sulfonylureas www.freelivedoctor.com

NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION www.freelivedoctor.com

Nonmicrosomal Oxidations Alcohol dehydrogenation is conducted by the enzyme alcohol dehydrogenase (cytosolic) Aldehyde dehydrogenation is conducted by the enzyme aldehyde dehydrogenase (cytosol and mitochondria) Xanthine oxidation is conducted by the cytosolic enzyme xanthine oxidase. Diamine oxidase (cytosolic) oxidizes histamine and diamines such as cadaverine and putrescine. Monoamine oxidation is conducted by mitochondrial monoamine oxidase (norepinephrine, epinephrine, dopamine and serotonin are endogenous substrates. www.freelivedoctor.com

Monoamine Oxidase Metabolism of Serotonin www.freelivedoctor.com

Some Popular Substrates of Monoamine Oxidase
Serotonin
Epinephrine
Norepinephrine
Dopamine
Tyramine (found in certain foods)

Diamine Oxidase cadaverine www.freelivedoctor.com

Alcohol Dehydrogenase
A soluble enzyme, found almost exclusively in the parenchymal cells of the liver
Converts ethanol to acetaldehyde
Converts methanol to formaldehyde
Converts ethylene glycol to its respective aldehyde metabolites
Is inhibited by pyrazole

Alcohol Dehydrogenase CH 3 CH 2 OH + NAD +  CH 3 CHO + NADH + H + ethanol acetaldehyde www.freelivedoctor.com

Aldehyde Dehydrogenase CH 3 CHO + NAD +  CH 3 COOH + NADH + H + acetaldehyde acetate www.freelivedoctor.com

XANTHINE OXIDASE www.freelivedoctor.com

Xanthine Oxidase www.freelivedoctor.com

REDUCTION www.freelivedoctor.com

Nitro Reduction Microsomes and cytosol www.freelivedoctor.com

Nitro Reduction www.freelivedoctor.com

Azo Reduction Microsomes and cytosol www.freelivedoctor.com

Alcohol Dehydrogenation Cytosol www.freelivedoctor.com

DIHYDROPYRIMIDINE DEHYDROGENASE
DPYD
Inactivates 5-fluorouracil by ring reduction
Inherited deficiency of this enzyme leads to 5-fluorouracil toxicity
Enzyme deficiency can be detected by enzymatic or molecular assays using white blood cells
5-fluorouracil www.freelivedoctor.com 5-Fluorouracil 5-Fluoro-5,6-dihydrouracil DPYD

HYDROLYSIS www.freelivedoctor.com

Amide Hydrolysis Microsomes and cytosol www.freelivedoctor.com

Ester Hydrolysis Microsomes and cytosol www.freelivedoctor.com

Ester Hydrolysis Microsomes and cytosol Enalaprit www.freelivedoctor.com

EPOXIDE HYDROLASE www.freelivedoctor.com

Epoxide Hydrolase
A microsomal enzyme

Epoxide Hydrolase www.freelivedoctor.com

PHASE II METABOLIC PATHWAYS www.freelivedoctor.com

D+ ENDO X D X + ENDO PHASE 2 METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com

PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis www.freelivedoctor.com

GLUCURONIDATION www.freelivedoctor.com

Uridine-5’-  -D-glucuronic Acid The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. Examples of such substrates are morphine and acetaminophen. www.freelivedoctor.com

UDP-  -D-Glucuronsyltransferase
Is also called glucuronyl transferase
A microsomal enzyme
Substrates are called aglycones
Conducts phase 2 metabolic reactions
Products are called glucuronides
Glucuronides formed
RN- G ; RO- G ; RCOO- G ; RS- G ; RC- G
Bilirubin is an endogenous substrate
Induced by phenobarbital

Glucuronidation of Benzoic Acid UGT= UDP-  -D-Glucuronsyltransferase www.freelivedoctor.com

Glucuronidation of Aniline www.freelivedoctor.com

Glucuronidation of p -Hydroxyacetanilid www.freelivedoctor.com

Morphine Metabolism A small amount of morphine undergoes N-demethylation Morphine  Morphine -6-glucuronide (active metabolite) Morphine  Morphine -3-glucuronide (inactive metabolite) www.freelivedoctor.com

Morphine Metabolism Morphine -3-glucuronide is the major metabolite www.freelivedoctor.com

Induction Of UDP-  -D-Glucuronyl Transferase
Induced by phenobarbital
Induced by 3-methylcholanthrene

Glucuronidation in the Cat
The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol

SULFATE CONJUGATION www.freelivedoctor.com

Sulfate Conjugation
Conducted by the soluble enzyme sulfotransferase
Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS)
Conjugates are ethereal in character
Noninducible

3’-Phosphoadenosine-5’-phosphosulfate (PAPS) The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate is acetaminophen. www.freelivedoctor.com

Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate www.freelivedoctor.com

MINOXIDIL METABOLISM MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) www.freelivedoctor.com MINOXIDIL (inactive) MINOXIDIL N-O-SULFATE (active metabolite)

Species Differences in Sulfate Conjugation
Some species are deficient in the sulfate conjugation pathway
Pig
Opposum

N-ACETYLATION www.freelivedoctor.com

N-Acetyltransferase
A soluble enzyme
Isoniazid is a substrate
Genetic variation occurs
Some individuals are fast acetylators
Some individuals are slow acetylators
Acetyl coenzyme A is the endogenous donor molecule

Acetyl CoA Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase. www.freelivedoctor.com

N-Acetyltransferase www.freelivedoctor.com

N-Acetyltransferase
The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT

SUGAR CONJUGATION www.freelivedoctor.com

Conversion of 6-Mercaptopurine to a Nucleotide www.freelivedoctor.com

METHYLATION www.freelivedoctor.com

S-Adenosylmethionine Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT. www.freelivedoctor.com

Methyltransferases
A family of soluble enzymes that conducts
N-methylation; N-CH 3
O-methylation; O-CH 3
S-methylation; S-CH 3
S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine

N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase www.freelivedoctor.com Norepinephrine Epinephrine PNMT SAM

O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase www.freelivedoctor.com

O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase www.freelivedoctor.com

S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent www.freelivedoctor.com

METABOLISM OF MERCAPTOPURINE (1)
TMPT -Thiomethylpurinetransferase
Conducts S-methylation of the substrate
Found in RBC’s
Isoforms exist
active enzyme
inactive enzyme
www.freelivedoctor.com 6-Mercaptopurine 6-Methylmercaptopurine TMPT

AMINO ACID CONJUGATION www.freelivedoctor.com

AMINO ACID CONJUGATION (mitochondria) www.freelivedoctor.com

Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.freelivedoctor.com

Salicyluric Acid is the Glycine Conjugate of Aspirin Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation. www.freelivedoctor.com

Acetyl Salicylic Acid (Aspirin) Metabolism
Salicylic acid the hydrolytic product of acetyl salicylic acid. Salicylic acid is further metabolized
Salicyl uric acid is the glycine conjugate and the main metabolite of aspirin. About 75% of aspirin is metabolized by this pathway
Other metabolites of aspirin
the acyl glucuronide conjugate of salicylic acid (salicylic acid glucuronide)
the phenol glucuronide conjugate of salicylic acid (salicyl phenol glucuronide)
the ring hydroxylated product of salicylic acid (gentisic acid)
the ring hydroxylated product of the glycine conjugate (gentisuric acid

TRANSULFURATION www.freelivedoctor.com

GLUTATHIONE CONJUGATION www.freelivedoctor.com

DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug www.freelivedoctor.com

MERCAPTURIC ACID FORMATION
Conjugation of substrate to glutathione by the enzyme glutathione transferase
Hydrolytic removal of glutamic acid by glutamyl transpeptidase
Hydrolytic removal of glycine by cysteinyl glycinase
Acetylation of the cysteinyl substrate by N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate”

ACETAMINOPHEN METABOLISM www.freelivedoctor.com

Bioactivation of Acetaminophen www.freelivedoctor.com

ACETAMINOPHEN AND ITS PHASE II METABOLITES The sulfate and glucuronide conjugates of acetaminophen are the major metabolites. High doses of acetaminophen can exhaust the metabolic pathways that produce these conjugates, allowing more of the parent drug to undergo the phase I metabolic pathway which is involved in bioactivation and toxication. www.freelivedoctor.com

ACETAMINOPHEN AND ITS PHASE I METABOLITES www.freelivedoctor.com

ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2 The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen , is always produced by microsomal cytochrome P450. It rearranges to the electrophile N-acetylbenzoquinoneimine, which in turn reacts with the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is the final metabolite. If tissue glutathione stores are depleted as a result of fasting, intake of excessive doses of acetaminophen or through induction of CYP2E1 as a result of chronic intake of ethanol, the quinone interacts with nucleophilic sites of cellular macromolecules, such as proteins. Liver necrosis is the result. Regular intake of acetaminophen during fasting or chronic ethanol intake should be avoided. N-acetylcysteine is the antidote for acetaminophen poisoning. It reacts with the electrophile. A small amount of acetaminophen is reported to undergo deacetylation to the phase 1 metabolite p -aminophenol. www.freelivedoctor.com

N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY www.freelivedoctor.com

CARCENOGENSIS www.freelivedoctor.com

N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com

Further Metabolism of N-HydroxyAAF Produces Cancer N-HydroxyAAF undergoes phase II metabolism to the ultimate carcingogen. The glucuronide pathway is also involved in carcinogenesis www.freelivedoctor.com

CYP1A1 Converts Benzopyrene to a Carcinogen www.freelivedoctor.com

Aflatoxin is Metabolized to a Carcinogenic Agent www.freelivedoctor.com

FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com

ENZYME INDUCTION www.freelivedoctor.com

Enzyme Induction - increased enzyme protein levels in the cell
Phenobarbital type induction by many drugs
Polycyclic hydrocarbon type induction by polycyclic hydrocarbons such as 3,4-benzopyrene and 3-methylcholanthrene

AGE www.freelivedoctor.com

FACTORS AFFECTING DRUG METABOLISM
Age
Neonates
Children
Elderly

DIET www.freelivedoctor.com

Diet
Charcoal broiled foods (contain polycyclic hydrocarbons that increase certain enzyme protein in cells)
Grapefruit juice (the active component is the furancoumarin 6,7-dihydroxybergamottin which inhibits a certain a group of microsomal enzymes)

GENETIC VARIATION www.freelivedoctor.com

Some Enzymes That Exhibit Genetic Variation
Pseudocholinesterase
typical enzyme
atypical enzyme
N-Acetyltransferase (isoniazid is a substrate)
fast acetylation
slow acetylation
Cytochrome P450 2D6
Cytochrome P450 2C19
TMPT -Thiomethylpurinetransferase
Dihydropyrimidine Dehydrogenase

STATE OF HEALTH www.freelivedoctor.com

State of health
Hepatitis
Liver cancer
Cardiac insufficiency
Uremia
degree of protein binding

Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action www.freelivedoctor.com

GENDER www.freelivedoctor.com

Gender
Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats

DEGREE OF PROTEIN BINDING www.freelivedoctor.com

Degree of protein binding
Conditions that displace bound drug from protein allows more of the drug to be accessible to the enzyme for which it serves as a substrate e.g. uremia, low plasma albumin

SPECIES VARIATION www.freelivedoctor.com

Species variation
Quantitative
Qualitative

Species variation
Human beings metabolize amphetamine by deamination; rats and dogs metabolize the drug by aromatic hydroxylation
Guinea pigs have very little sulfotransferase activity, humans have substantial activity
Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do
Hexobarbital is metabolized at different rates by different species

SUBSTRATE COMPETITION www.freelivedoctor.com

Substrate competition
Two or more drugs competing for the same enzyme can affect the metabolism of each other; the substrate for which the enzyme has the greater affinity would be preferentially metabolized

Drug metabolism

by raj kumar

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