3837biotransformation (Metabolism) of Drugs

Biotransformation (Metabolism) of Drugs
A.
General properties
1. Biotransformation is a major mechanism for drug elimination; Results of biotransformation: Production of metabolites that are more polar than the parent drug usually terminates the pharmacologic action of the parent drug After phase I reactions, similar or different pharmacologic activity, or toxicologic activity.
Results of biotransformation
2.
Many drugs undergo

several sequential biotransformation reactions. Biotransformation is catalyzed by specific enzyme systems
3.
Sites of biotransformation:
The liver: the major site other tissues.
4. Biotransformation of drugs can be affected by many parameters, including:

A. B. C. D. E. F. G. prior administration of the drug in question or of other drugs diet hormonal status genetics disease (e.g., decreased in cardiac and pulmonary disease) age and developmental status liver function
5. Possible consequences of biotransformation include the production of:

inactive metabolites (most common) metabolites with increased or decreased potencies metabolites with qualitatively different pharmacologic actions toxic metabolites active metabolites from inactive prodrugs.
Metabolites are often more polar than the parent compounds. This increased polarity may lead to: a more rapid rate of clearance because of possible secretion by acid or base carriers in the kidney
it may lead to decreased tubular reabsorption.
B.
Classification of biotransformation reactions
1. Reactions that involve enzyme-catalyzed biotransformation of the drug without any conjugations. Phase I reactions include:
oxidations reductions hydrolysis reactions
they introduce a functional group (e.g., -OH) that serves as the active center for sequential conjugation in a phase II reaction.
2. Reactions that include conjugation reactions, which involve the enzyme-catalyzed combination of a drug (or drug metabolite) with an endogenous substance. Phase II reactions require: a functional groupan active centeras the site of conjugation with the endogenous substance.
energy indirectly for the synthesis of activated carriers, the form of the endogenous substance used in the conjugation reaction (e.g., UDP-glucuronate).
Drug metabolism reactions :
C.
Enzymes catalyzing phase I biotransformation reactions
Enzymes catalyzing phase I biotransformation reactions include: cytochrome P-450 aldehyde and alcohol dehydrogenase deaminases esterases amidases epoxide hydratases
Enzymes catalyzing phase II biotransformation reactions include: glucuronyl transferase (glucuronide conjugation) sulfotransferase (sulfate conjugation) transacylases (amino acid conjugation) acetylases ethylases methylases glutathione transferase.
Location of these enzymes:

numerous tissues some are present in plasma.
Subcellular locations include:

cytosol mitochondria endoplasmic reticulum
Only those enzymes located in the endoplasmic reticulum are inducible by drugs
1.
Cytochrome P-450 monooxygenase (mixed function oxidase)
a.
General features A large number of families (at least 18 in mammals) of cytochrome P-450 (abbreviated CYP) enzymes exists each member of which catalyzes the biotransformation of a unique spectrum of drugs some overlap in the substrate specificities.
This enzyme system is the one most frequently involved in phase I reactions.
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc. Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc. The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Cytochrome P-450 catalyzes numerous reactions, including: aromatic and aliphatic hydroxylations dealkylations at nitrogen, sulfur, and oxygen atoms heteroatom oxidations at nitrogen and sulfur atoms reductions at nitrogen atoms ester and amide hydrolysis
The CYP3A subfamily is: responsible for up to half of the total cytochrome P450 in the liver
accounts for approximately 50% of the metabolism of clinically important drugs.

CYP3A4 is a particularly abundant enzyme.
representative P450 isozymes.
b. Localization The primary location of cytochrome P-450 is the liver, Other tissues, including:
the adrenals ovaries and testis tissues involved in steroidogenesis and steroid metabolism.
The enzyme's subcellular location is the endoplasmic reticulum.
c. 1.
Mechanism of reaction In the overall reaction:

the drug is oxidized oxygen is reduced to water.
Reducing equivalents are provided by nicotinamide adenine dinucleotide phosphate (NADPH), and generation of this cofactor is coupled to cytochrome P-450 reductase.
d.
Genetic polymorphisms Genetic polymorphism of several clinically important cytochrome P-450s, particularly CYP2C and CYP2D, is a source of variable metabolism in humans, including differences among racial and ethnic groups. These enzymes have substantially different properties (Vmax or Km).
e. Induction of drug metabolism :

Enzyme synthesis initiated within 24 h of exposure, increasing over 3 5 days Effect decreases over 1 3 weeks after inducing agent is discontinued Environmental Factors:
Cigarette smoking eating BBQ meat cruciferous veggies (plants in the mustard family which includes the cabbage, radish, broccoli, and many weeds.) high protein diet Ethanol exposure to insecticides (DDT, Lindane) & PCBs
(polychlorinated biphenyls)
Other drugs:
Barbiturates Phenytoin Carbamazepine Rifampicin dexamethasone
f. Inhibition
Rapid onset within 1 day Competitive or noncompetitive (clinically more likely) inhibition of P-450 enzyme activity can result in the reduced metabolism of other drugs or endogenous substrates such as testosterone. Inhibition can be caused by a number of commonly used drugs, including:
Cimetidine fluconazole Fluoxetine Erythromycin
grapefruit juice.
Glucuronyl Transferse
1. General features Glucuronyl transferase is a set of enzymes with unique but overlapping specificities that are involved in phase II reactions. It catalyzes the conjugation of glucuronic acid to a variety of active centers, including:
-OH -COOH -SH -NH2
2. Mechanism of reaction
UDP-glucuronic acid, the active glucuronide donor, is formed from UTP and glucose 1-phosphate. Glucuronyl transferase then catalyzes the conjugation to the active center of the drug.
3. Location and induction

Glucuronyl transferase is located in the endoplasmic reticulum. It is the only phase II reaction that is inducible by drugs and is a possible site of drug interactions.
Metabolism of phenytoin :
Inhibitors of intestinal P glycoprotein:

P-glycoprotein (P-gp) has been identified as an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen.
Drugs that inhibit intestinal P-gp mimic drug metabolism inhibitors by increasing bioavailability and may result in toxic plasma concentrations of drugs given at normally nontoxic dosage.
P-gp inhibitors include: Verapamil grapefruit juice
Important drugs that are normally expelled by P-gp (and which are therefore potentially more toxic when given with a P-gp inhibitor) include digoxin, cyclosporine, and saquinavir.
Metabolism of acetaminophen to harmless conjugates or to toxic metabolites.
nontoxic phase II conjugates
nontoxic phase II conjugates phase I Reaction
Ac* production increases: 1. Depletion of hepatic stores of sulfate, glucuronide, and glutathione 2. Overwhelm phase II rxns 3. Induction of phase I enzymes
toxic
nontoxic phase II conjugates

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Biotransformation (Metabolism) of Drugs

Many drugs undergo

4. Biotransformation of drugs can be affected by many parameters, including:

5. Possible consequences of biotransformation include the production of:

it may lead to decreased tubular reabsorption.

Classification of biotransformation reactions

Drug metabolism reactions :

Enzymes catalyzing phase I biotransformation reactions

Location of these enzymes:

Subcellular locations include:

Cytochrome P-450 monooxygenase (mixed function oxidase)

accounts for approximately 50% of the metabolism of clinically important drugs.

representative P450 isozymes.

The enzyme's subcellular location is the endoplasmic reticulum.

Mechanism of reaction In the overall reaction:

e. Induction of drug metabolism :

3. Location and induction

Inhibitors of intestinal P glycoprotein:

P-gp inhibitors include: Verapamil grapefruit juice

Metabolism of acetaminophen to harmless conjugates or to toxic metabolites.

nontoxic phase II conjugates

nontoxic phase II conjugates phase I Reaction

nontoxic phase II conjugates

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