Lecture 5 - Drug Metabolism - 12 Sep 2006

Elimination of Drugs Metabolism I. F. Benter Pharmacology & Toxicology Faculty of Medicine Kuwait University

Renal excretion terminates the actions of relatively few drugs, such as:  Small drugs  Those that remain fully or nearly fully ionized at physiological pH  Those that are NOT protein bound

However, most pharmacologically active molecules tend to be:  Lipohilic  Remain unionized or only partially ionized at physiological pH  Often bound strongly to plasma proteins These are NOT good candidates for renal Elimination. Metabolism is the more important mechanism of termination for most drugs

 Lipophilic, unionized or bound drugs would remain in the body for prolonged periods if their actions were not terminated by some alternate process  Example - Pentobarbital  Highly lipophilic anesthetic agent  Would exert its pharmacological effect for 100 years if it weren’t for drug metabolism.

 In general, most drugs are metabolized into molecules that are more water soluble  Usually, drug metabolites are less active pharmacologically than the parent compound. the rate of drug metabolism is the primary determinant of both duration and intensity of drug action

Drug Metabolism  Most metabolism occurs in the liver  Certain other organs and tissues can metabolize substances  GI mucosa  Lower bowel – microorganisms may play a major role  kidneys

 skin

 lung

 Others – e.g. nasal mucosa

Drug Metabolism  Enzyme involved are distinct from those that breakdown foodstuffs.  Drugs absorbed from the GI tract are first transported to the liver via the portal vein.  When drugs are extensively metabolized during the initial pass through the liver, it is called first pass effect.

 Many drug metabolizing enzymes are located in the endoplasmic reticulum of the liver and other tissues.  Drug metabolism reactions are divided into two main categories:  Phase I

 Phase II

Drug Metabolism: Phase I  Converts drug to a more polar compound by unmasking or inserting a functional group (eg. oxidation, reduction, hydrolysis) Metabolites may still NOT be sufficiently water soluble for renal excretion. Many undergo phase II reactions to increase water solubility even further.

Phase I Reactions  Performed by the mixed function oxidases or cytochrome P450 system  Present in the smooth endoplasmic reticulum of liver cells

Major P-450 Isoforms  CYP1A2, CYP2A6, CYP2C6, CYP2C9  CYP3A4 – responsible for more than 60% of drugs metabolized by the liver

 N-Dealkylation RNHCH3

RNH2 + CH2O

Examples : Imipramine, diazepam, codeine, erythromycin, morphine, tamoxifen, theophylline

Drug Metabolism:

Phase II

 Increase polar nature of the compound by adding an endogenous substance Example: conjugation with glucuronic acid or sulfate  Some of the conjugation products may undergo a phase I reaction.  Synthetic reactions – couples drug with an endogenous substance

III. Conjugation Reactions  Glucuronidation COOH

COOH

O +R

OH OH

OH

OH

UDP

+ UDP

OH OH

O

R

OH

UDP-glucuronide acid

Examples : Acetaminophen, morphine

 Endogenous substances  Glucorinic acid  Sulfate  Glycine  Acetate  This often occurs to substances that have undergone phase I metabolism

Phase 1 Drug

Phase 2 Derivative

Conjugate OH

Hydroxylation

Conjugation HO

COOH OCOCH3

Aspirin

COOH

COOH O

OH

Salicilylic acid

Glucuronide

OH

COOH

Example of the whole system  benzene – very lipid soluble  first hydroxylated by phase I reactions to phenol  Hydroxylation doubles (2X) the elimination of the compound  Phenol is then conjugated with sulfate and glucuronic acid (phase II)  Resulting compound has an excretion rate which is 10 to 20 fold greater than benzene

Induction of Metabolism  Inducers enhance the rate of P450 synthesis and / or reduce its degradation.  Various isoenzymes may be induced selectively  induced forms may differ from original  many therapeutic agents induce metabolism  many environmental substances also induce metabolism

Inhibition  Certain substances inhibit cytochrome P450 activity  Some substances such as certain macrolide antibiotics (e.g. erythromycin) irreversibly inhibit the P450 reactions  Imidazoles such as cimetidine, or ketoconazole bind to cytochrome oxidase and therefore inhibit metabolism competitively