BIOC 3310 - Drug Metabolism

Drug metabolism requires enzymes similar to those of

other cellular metabolic reactions

Enzymes are classified according to the

reaction they catalyze.

Oxidoreductases

catalyze oxidation-reduction reactions

Transferases

transfer functional groups

Hydrolases

hydrolysis reactions

Lyases

group elimination to form double bonds

Isomerases

Isomerization

Ligases

bond formation coupled with ATP hydrolysis

Biological outcomes of drug metabolism

Inactivation, Detoxification, Activation, Trans-activation, or Toxification

§Inactivation (deactivation) and accelerated elimination of drugs

Eliminate

drug actions, and the drug metabolites are excreted by kidney or feces

Detoxification

Drugs become

less toxic and excreted by kidney or feces

Activation of prodrugs

Prodrugs are biologically inactive compound and turns into

active drugs by metabolic enzymes

Trans-activation or formation of active metabolites with similar or novel activity

Drugs and their metabolites are both able to bind to their

intended or new biological targets

Toxification

Drug metabolites are

toxic

Types of reactions in drug metabolism:

Most common ones are:

Oxidation, Reduction, Hydrolysis, and conjugation

Oxidation -> ____ drug metabolism

Phase I

Reduction -> ____ drug metabolism

Phase I

Hydrolysis -> ____ drug metabolism

Phase I

Conjugation -> ____ drug metabolism

(classified as "transferases")

Phase II

drug metabolism often, though not necessarily, takes place in

two steps.

Drug metabolites are generally more

polar

Hydrolysis of an ester, the enzyme is called

esterase

Hydrolysis of an amide, the enzyme is called

amidase

Drug-Drug interaction - is the drug coadministered makes others affected in

pharmacokinetics, with absorption, metabolism, elimination

Phase I oxidation reactions catalyzed by many oxidases (enzymes), Don't forget that it is an enzymatic reaction and requires

coenzymes

Cytochrome P450

• contain a heme (Fe) group

• absorb light at 450 nm

• many CYPs: polymorphic distribution of activity

- has many

enzymes, is a family, each with different substrates

Cytochrome P450 Polymorphism

PM = poor metabolizers, has

adverse effects

IM = intermediate metabolizers

has an exaggerated response, with adverse effects

EM= extensive metabolizers

expected response

URM = ultra rapid metabolizers

lack of response

Different substrate and reactions that are catalyzed by cytochrome P450: Aliphatic oxidation, Don't forget that it is an enzymatic reaction and requires coenzymes

(NADPH, FADH2, FMNH2).

Summary: Phase I oxidation reactions by CYP450

- Aromatic oxidation

- Aliphatic oxidation

- Epoxidation

- Oxidative de-alkylation

-Oxidative de-amination

Aromatic oxidation

Adding

OH to para-position

Aliphatic oxidation

Adding OH to the end of the

alkyl group (primary alcohol)

Epoxidation

Adding -O- group to C=C, then further into

(OH)-C-C-(OH)

Oxidative de-alkylation

Alkyl group is removed, the hetro-atom (N,S,O) has

H instead

Oxidative de-amination

NH2 is removed, the carbon that N-previously attached become

C=O

What happens if you are a poor metabolizer?

There will be no action of drug/nothing will change

What happens if you are an ultrarapid metabolizer?

can convert to morphine very fast, high concentration absorbed

Erythromycin and ketoconazole are inhibitors of

CYP 3A4 activity

Co-administration of these drugs with other drugs that are metabolized by CYP 3P4 could result in an increase in

their concentrations

This is part of drug-drug interaction phenomena.

Grapefruit juice can inhibit intestinal CYP3A4, thereby increasing the amount of drug that reaches the

liver and the systemic circulation

This is part of drug-food interaction phenomena.

Phase 2 reactions:

1.Glucuronic acid conjugation

-Drugs carrying a hydroxyl group (-OH)

-Enzymes called glucoronic acid transferases

-Co-enzyme called UDPGA

Phase II Reactions:

2. Sulfate conjugation (sulfation)

- Drugs carrying a hydroxyl group (-OH) or a carboxylic group (-COOH)

- Enzymes called sulfotransferases

- Co-enzyme called PAPS (phosphoadenosylphosphosulfate)

3. Glutathione conjugation

- Drugs carrying highly reactive group that could form a reactive radical

- Enzymes called glutathione S-transferase

- Co-enzyme called Glutathione

4. Acetylation

- Drugs carrying a primary amine (-NH2)

- Enzymes called acetyl-transferases

- Co-enzyme called Acetyl CoA

5. Methylation

- Drugs carrying a primary amine (-NH2), hydroxyl (-OH) or thiol (-SH)

- Enzymes called methyl-transferases

- Co-enzyme called S-adenosylmethionine

Multiple reactions can simultaneously work on

one drug