Drug Metabolism Consequences of Drug Metabolism

Drug Enzyme (E) Metabolites

(D) Substrates (s) (DS)
MAJOR
Active Inactive
Less Lipid Soluble
Dr. Robert G. Lamb more readily excreted
MINOR
Professor Inactive Active

Pharmacology & Toxicology Toxic Non-toxic

Non-toxic Toxic

Active Equal, less

or more active

Effect of Enzyme Level on Activity

Influence of Substrate on Enzyme Activity

Increasing enzyme concentration

4x

Amount of substrate transformed

E + S ↔ ES → P
E + S ↔ ES → P
3x

2x

1x

Time of reaction

Cellular Location of Drug Metabolizing Enzymes

Overall Metabolism Scheme

reduction

1
 Hydrolysis of Aspirin
Hydrolysis of Procaine
E = plasma esterase H2N O C2H5
O
E Short-acting local
C O CH2 CH2 N
R – C – OR R - COOH + ROH anesthetic
acid alcohol C2H5
procaine
(novocaine)
E = plasma esterase
O
O
O C CH3 E OH
+ HO C CH3
COOH COOH
H2N O C2H5
aspirin salicylic acid acetic acid
C O + HO CH2 CH2 N
H
C2H5
Hydrolysis of Aspirin para-aminobenzoic diethylamino-
acid (PABA) ethanol

Procaine Hydrolysis
Amide Hydrolysis

Lidocaine Hydrolysis
Reduction of Chloral Hydrate

2
 Overall Scheme of Oxidative Metabolism
P450-Dependent Drug Oxidation
NADP+ NADPH+
Non-specific system associated with ER
P 450 1- Substrate Binding
Multiple forms of CYP-P450 [enzyme] Flavoprotein
Reductase
Flavoprotein
(reduced) (oxidized)
1A2[12%] induced by Smoking and Charcoal Cooking 2 2- Substrate Reduction
2B6 [20%] induced by Phenobarbital (PB) and Rifampin e-

2E1 [6%] induced by Alcohol and Isoniazid 3- Substrate Oxygenation

3A4 [28%] induced by PB, Phenytoin, Rifampin, etc. RH P -4 5 0 -F e 2 +

e-
3- Substrate Reduction
3
RH P -4 5 0 -F e 3 + O2

NADPH Cytochrome P450 reductase [enzyme] RH P -4 5 0 -F e 2 +

O2
H 2O
4- Substrate Rearrangement
Substrates: Oxygen, NADPH and Drug
1 4
P -4 5 0 -F e 3 +

R-H
(parent drug)
R-OH
(oxidized product) 4- Product Dissociation

Examples of Oxidative Metabolism I

Regulation of Oxidative Metabolism
N-Oxidation Aniline
Primary amines RNH 2 RNHOH chlorphentermine
1. Level of CYP-P450 and Reductase Enzymes
Higher in alcoholics and smokers (more drug) Secondary amines 2-Acetylamino-
R1 R1
fluorene,
Higher with drug intake (PB etc.) [more drug] NH N OH acetaminophen.
Lower in elderly, infants (less drug) R2 R2

2. Level of substrates (drugs, oxygen and NADPH) Tertiary amines Nicotine,

R1 R1
methaqualone
R2 N R2 N O
R3 R3

Examples of Oxidative Metabolism II

Role of Phase I and II Reactions
S-Oxidation R1 R1 Thioridazine,
cimetidine,
S S O chlorpromazine
Phase I reactions usually precede Phase II reactions.
R2 R2

Deamination OH Amphetamine, Phase I reactions produce chemically reactive sites.

diazepam.
RCHCH 3 R C CH3 R CCH 3 + NH 3

NH2 NH2 O
Phase II reactions occur at reactive sites.

Desulfuratio
R1 R1
Thiopental. Phase II metabolites are usually inactive.
n
C S C O
R2 R2

3
 Glucuronidation of Aspirin
Acetylation of Sulfanilamide
NH2 NH CO CH3
N - AT
+ HOOC CH3
UDPG is UDP-glucuronic acid
SA = salicylic acid
E is glucuronosyl transferase SO2NH2 SO2NH2
metabolite of aspir
Sulfanilamide Acetic Acid Acetylsulfanilamide
OH E OC6H9O6
COOH UDPG COOH N-AT is N-Acyltransferase

SA ether glucuronide of SA
10%

Glycine Conjugation of Aspirin Metabolite (SA) Methylation Reactions

HO OH CH3 OMT CH3O OH CH3
OH N - AT OH CH CH2 NH CH CH2 NH
+ H 2N CH2 COOH HO SAM HO
COOH CONH CH 2 COOH

SA epinephrine metanephrine
(salicylic acid) glycine salicyluric acid

75% major HO OH NMT HO OH CH3

metabolite of Aspirin HO CH CH2 NH2 SAM HO CH CH2 NH

norepinephrine epinephrine

O-, N-methyltransferase (OMT & NMT)

S-Adenosylmethionine (SAM)

Acetaminophen Hepatotoxicity
ACETAMINOPHEN
HNCOCH3 HNCOCH3
PAPS UDPGA HNCOCH3
Factors Influencing Drug Metabolism I
SULFATE OH GLUCURONIDE Enzyme Induction (slow) increases drug clearance
45 - 50% P-450 MIXED FUNCTION OXIDASE
45 - 50%
HO-N-COCH3
Diseases: Hyperthyroidism
OXIDATIVE STRESS (•OH, O 2 •–)
4 - 5% POSTULATED
OH
LOW DOSE (1-2g)
TOXIC
INTERMEDIATES
Drugs [many]: PB, Rifmpin, Phenytoin, etc.
Key Factor NCOCH3 HIGH DOSE (10-15g)
GLUTATHIONE NUCLEOPHILIC CELL
MACROMOLECULES Conditions: smoking, alcoholism
1+
HNCOCH3 HNCOCH3
O

GLUTATHIONE CELL Higher doses of drugs are required

MACROMOLECULES
OH OH

Alcoholic Only one induction period then stable level

MERCAPTURIC CELL
ACID N-Acetylcysteine DEATH

4
 Factors Influencing Drug Metabolism II Factors Influencing Drug Metabolism III

Enzyme Inhibition (fast) reduces drug clearance Age: low metabolism in elderly and newborn

Diseases:Hypothyroidism, Liver Disease start low and go slow with drug dose

Drugs (many): Chloramphenicaol, Cimetidine,

Disulfiram, Ethanol (acute), etc. Nutrition: high metabolism with chronic intake of alcohol

Conditions: Pregnancy, Aging, Newborn and charcoal cooked food and lower with high

acute alcohol intake.

Factors Influencing Drug Metabolism IV

Genetic Variations:

Isoniazid [prophylaxis of tuberculosis] produces liver

injury in slow acetylators.

Succinylcholine [surgical muscle relaxant] produces

prolonged respiratory depression (apnea) in
patients with abnormal plasma cholinesterase
which reduces the hydrolysis of succinylcholine.