Pharmacology and Therapeutics Lecture #4
DRUG METABOLISM, DRUG EVALUATION, & REGULATION
OUTLINE:
I. DRUG METABOLISM OR BIOTRANSFORMATION
A. Phase 1 or Functionalization
B. Phase 2 or Conjugation
II. SITES OF DRUG METABOLISM
A. Kidney
B. Blood
C. Gastrointestinal tract
III. DETERMINANTS OF
BIOTRANSFORMATION RATE
A. Race
B. Drug-drug interactions
C. Age
D. Presence of co-morbidities
E. Gender
IV. MECHANISMS INVOLVED IN DRUG- Phase I Reactions
DRUG INTERACTIONS
A. Enzyme Induction ◼ Oxidation
B. Enzyme Inhibition ◼ Reduction
C. Inhibitors of Intestinal P-Glycoprotein ◼ Hydrolysis
V. TOXIC METABOLISM
VI. References Substrate molecules changes
Polarity increases by insertion of polar functional
groups (-OH, -SH, -NH2)
Substrate gains a suitable structure for phase 2 rxns
DRUG METABOLISM / BIOTRANSFORMATION
Metabolic pathways taken by individual
drug molecules
Phase II Metabolism
Drug interactions
Mechanism that regulate the flow of ◼ Glucuronic acid conjugation/ Glucuronidation
metabolites through pathways ◼ Glycine conjugation
Sum of all the chemical reactions for ◼ Ethereal Sulfate conjugation
biotransformation of endogenous and exogenous ◼ Methylation
substances which take place in the living cell ◼ Acetylation
◼ Glutathione conjugation
Xenobiotics
- substances absorbed across the lungs or skin or, Most of these groups are relatively polar and make the
more commonly, ingested either unintentionally as product less lipid-soluble that the original drug
compounds present in food and drink or deliberately as molecule by conjugation with a polar moiety such as
drugs for therapeutic or “recreational” purposes. glucoronate, acetate, sulfates, etc.
BIOTRANSFORMATION of DRUGS
Chemical modification of drugs
An important mechanism for drug inactivation
Main fxn: formation of more polar and water-
soluble compounds resulting in reduction of their
pharmacological activity and more rapid excretion
from the body
Other fxn: serves to activate prodrugs
Prodrugs
- a pharmacologically inactive substance that is
converted in the body (such as by enzymatic action)
into a pharmacologically active drug.
Drugs that are metabolized by both routes may
undergo phase II metabolism before or after phase I.
Morphine
-undergoes phase 2 first before being excreted
from the kidney
STUDYPOOL NOTEBANK` Page 1 of
, Pharmacology and Therapeutics Lecture #4
DRUG METABOLISM, DRUG EVALUATION, & REGULATION
EXAMPLES OF PHASE II DRUG-METABOLIZING
Isoniazid RXN
-undergoes phase II first then converted in phase I Reaction Type Common Drug Substrates
before being excreted Acetaminophen
Gentamycin Diazepam
-does not undergo phase I and II Glucuronidation Digoxin
metabolism (remains unchanged Morphine
when excreted) Sulfamethiazole
Clonazepam
EXAMPLES OF PHASE I DRUG-METABOLIZING RXN Dapsone
Acetylation Isoniazid
Reaction Type Common Drug Substrates Mescaline
Sulfonamides
Oxidation CYP450 dependent
Ethacrynic acid, phase I
Amphetamines Glutathione conjugation
metabolite of acetaminophen
Hydroxylation Barbiturate Deoxycholic acid
Phenytoin Glycine conjugation Nicotinic acid (niacin)
Caffeine Salicylic acid
N - Dealykylation Morphine Acetaminophen
Theophylline Sulfation Estrone
O - Dealykylation Methyldopa
Codeine
Dopamine
Acetaminophen
N - Oxidation Epinephrine
Nicotine
Methylation Histamine
Chlorpromazine
Norepinephrine
S - Oxidation Cimetidine
Thiouracil
Thioridazine
Acetaminophen
Deamination
Diazepam
PHASE 1 ENZYMES PHASE 2 ENZYMES
Oxidation CYP450 independent
Amine Oxidation Epinephrine Cytochrome P450 Uridine diphosphate -
Chloralhydrate Monooxygenase Glucuronosyltransferase
Dehydrogenation (CYP450) (UDPGT)
Ethanol
Chloramphenicol
Flavin-containing
Clonazepam Sulfotransferase (ST)
Reduction monooxygenase (FMO)
Dantrolene
Naloxone N-Acetyltransferase
Esterase
Hydrolyses (NAT)
Aspirin
Alcohol dehydrogenase Glutathione s-Transferase
Clohbrate
Esters (ADH) (GST)
Procaine
Succinylcholine Aldehyde dehydrogenase
Indomethacin Methyltransferase
(ALDH)
Amides Lidocaine
Procainamide Monoamine Oxidase
Amino acid conjugation
(MAO)
SITE OF DRUG METABOLISM
Principal site of drug metabolism is - LIVER
Less important are the kidney, GI tract and blood
STUDYPOOL NOTEBANK` Page 2 of
DRUG METABOLISM, DRUG EVALUATION, & REGULATION
OUTLINE:
I. DRUG METABOLISM OR BIOTRANSFORMATION
A. Phase 1 or Functionalization
B. Phase 2 or Conjugation
II. SITES OF DRUG METABOLISM
A. Kidney
B. Blood
C. Gastrointestinal tract
III. DETERMINANTS OF
BIOTRANSFORMATION RATE
A. Race
B. Drug-drug interactions
C. Age
D. Presence of co-morbidities
E. Gender
IV. MECHANISMS INVOLVED IN DRUG- Phase I Reactions
DRUG INTERACTIONS
A. Enzyme Induction ◼ Oxidation
B. Enzyme Inhibition ◼ Reduction
C. Inhibitors of Intestinal P-Glycoprotein ◼ Hydrolysis
V. TOXIC METABOLISM
VI. References Substrate molecules changes
Polarity increases by insertion of polar functional
groups (-OH, -SH, -NH2)
Substrate gains a suitable structure for phase 2 rxns
DRUG METABOLISM / BIOTRANSFORMATION
Metabolic pathways taken by individual
drug molecules
Phase II Metabolism
Drug interactions
Mechanism that regulate the flow of ◼ Glucuronic acid conjugation/ Glucuronidation
metabolites through pathways ◼ Glycine conjugation
Sum of all the chemical reactions for ◼ Ethereal Sulfate conjugation
biotransformation of endogenous and exogenous ◼ Methylation
substances which take place in the living cell ◼ Acetylation
◼ Glutathione conjugation
Xenobiotics
- substances absorbed across the lungs or skin or, Most of these groups are relatively polar and make the
more commonly, ingested either unintentionally as product less lipid-soluble that the original drug
compounds present in food and drink or deliberately as molecule by conjugation with a polar moiety such as
drugs for therapeutic or “recreational” purposes. glucoronate, acetate, sulfates, etc.
BIOTRANSFORMATION of DRUGS
Chemical modification of drugs
An important mechanism for drug inactivation
Main fxn: formation of more polar and water-
soluble compounds resulting in reduction of their
pharmacological activity and more rapid excretion
from the body
Other fxn: serves to activate prodrugs
Prodrugs
- a pharmacologically inactive substance that is
converted in the body (such as by enzymatic action)
into a pharmacologically active drug.
Drugs that are metabolized by both routes may
undergo phase II metabolism before or after phase I.
Morphine
-undergoes phase 2 first before being excreted
from the kidney
STUDYPOOL NOTEBANK` Page 1 of
, Pharmacology and Therapeutics Lecture #4
DRUG METABOLISM, DRUG EVALUATION, & REGULATION
EXAMPLES OF PHASE II DRUG-METABOLIZING
Isoniazid RXN
-undergoes phase II first then converted in phase I Reaction Type Common Drug Substrates
before being excreted Acetaminophen
Gentamycin Diazepam
-does not undergo phase I and II Glucuronidation Digoxin
metabolism (remains unchanged Morphine
when excreted) Sulfamethiazole
Clonazepam
EXAMPLES OF PHASE I DRUG-METABOLIZING RXN Dapsone
Acetylation Isoniazid
Reaction Type Common Drug Substrates Mescaline
Sulfonamides
Oxidation CYP450 dependent
Ethacrynic acid, phase I
Amphetamines Glutathione conjugation
metabolite of acetaminophen
Hydroxylation Barbiturate Deoxycholic acid
Phenytoin Glycine conjugation Nicotinic acid (niacin)
Caffeine Salicylic acid
N - Dealykylation Morphine Acetaminophen
Theophylline Sulfation Estrone
O - Dealykylation Methyldopa
Codeine
Dopamine
Acetaminophen
N - Oxidation Epinephrine
Nicotine
Methylation Histamine
Chlorpromazine
Norepinephrine
S - Oxidation Cimetidine
Thiouracil
Thioridazine
Acetaminophen
Deamination
Diazepam
PHASE 1 ENZYMES PHASE 2 ENZYMES
Oxidation CYP450 independent
Amine Oxidation Epinephrine Cytochrome P450 Uridine diphosphate -
Chloralhydrate Monooxygenase Glucuronosyltransferase
Dehydrogenation (CYP450) (UDPGT)
Ethanol
Chloramphenicol
Flavin-containing
Clonazepam Sulfotransferase (ST)
Reduction monooxygenase (FMO)
Dantrolene
Naloxone N-Acetyltransferase
Esterase
Hydrolyses (NAT)
Aspirin
Alcohol dehydrogenase Glutathione s-Transferase
Clohbrate
Esters (ADH) (GST)
Procaine
Succinylcholine Aldehyde dehydrogenase
Indomethacin Methyltransferase
(ALDH)
Amides Lidocaine
Procainamide Monoamine Oxidase
Amino acid conjugation
(MAO)
SITE OF DRUG METABOLISM
Principal site of drug metabolism is - LIVER
Less important are the kidney, GI tract and blood
STUDYPOOL NOTEBANK` Page 2 of
