Session VI

Pro-drug, Biotransformation of drugs, enzyme induction, enzyme inhibition

and Entero-hepatic circulation.

Aphasia

DR. GHULAM SAQULAINM.B.B.S., D.L.O., F.C.P.SHEAD OF DEPARTMENT OF ENTCAPITAL HOSPITAL, ISLAMABAD

PRODRUG Prodrug is an inactive substance/drug that is

converted to a drug within the body by the action of enzymes or other chemicals.

About 5-7% of drugs approved worldwide can be classified as prodrugs

Rationale for Prodrug DesignA. Improving Formulation and AdministrationB. Enhancing Permeability and AbsorptionC. Changing the Distribution ProfileD. Protecting from Rapid Metabolism and ExcretionE. Overcoming Toxicity ProblemsF. Managing the Life Cycle

The prodrug approach is a strategy to increase the utility of pharmacologically active compounds, because one can optimize any of the properties as well as prolong the commercial life cycle of potential drug

Phosphate esters are a widely used prodrug strategy for improving the aqueous solubility. The active parent drug molecule is rapidly released from phosphate prodrugs by endogenous phosphatases, such as alkaline phosphatase.

Prednisolone sodium phosphate is a classic example of a phosphate prodrug It is a highly water-soluble

Also masks the unpalatable taste of prednisolone tablets.

BIO TRANSFORMATION (Drug Metabolism)

Definition

Chemical reactions which lead to modification of drugs.

Importance of metabolism Termination of drug action Enhance excretion by transforming the drug to a less lipid

soluble, less readily reabsorbed form.

Organ sites of drug metabolism

Liver (the major site). Intestinal Mucosa and Lumen Kidney Skin Lung Plasma

TYPES OF METABOLIC REACTIONS

Phase I Reactions

Phase II Reactions

Phase I reactions Oxidation. Reduction. Hydrolysis.

Phase II reactions Conjugation reactions

Oxidation ReactionsMicrosomal oxidation (CYT-P450).Oxidation by cytochrome P450 enzymes

Non-microsomal oxidation.

Oxidation by soluble enzymes in cytosol or

mitochondria of cells (as oxidases and

dehydrogenases) e.g. monoamine oxidase (MAO)

and alcohol dehydrogenase .

Reduction reactions Microsomal reduction Non microsomal reduction

Hydrolysis All are non microsomal Drugs affected are either esters or amides Hydrolysis occurs by enzymes (esterases or

amidases) e.g. acetylcholine and lidocaine

Phase I reactions can result in

Inactivation of drug (termination of action) Conversion of active drug to another active

metabolite. Conversion of drugs to toxic metabolites. Paracetamol acetaminophen hepatotoxicity Activation of pro-drug Product might undergo phase II.

Conjugation of metabolite (phase I) with

endogenous substance as methyl group, acetyl

group, sulphate, amino acid or glucouronic

acid to produce conjugate that is water soluble

and easily excreted.

Phase II Conjugation Reactions

Types of conjugation reactions

Conjugation reaction Enzyme required

glucouronide conjugation glucouronyl transferase

Acetylation N-acetyl transferase

Sulphation Sulfotransferase

Methylation methyl transferase

Amino acids conjugation

Phase II reactions:

All are non microsomal except

glucouronidation

Deficieny of glucouronyl transferase enzyme in

neonates may result into toxicity with

chloramphenicol (Gray baby syndrome).

Characteristics of Phase II Products

Usually make drug Pharmacologically inactive.

Polar more water soluble. more readily excreted in urine.

Factors affecting metabolism Age Nutrition Genetic Variation Diseases Gender Degree of Protein Binding Enzyme Induction & inhibition Route of Drug Administration

ENZYME INDUCTION Enzyme induction is a process in which a

molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme.

ENZYME INHIBITION Enzyme inhibition can refer to the inhibition of

the expression of the enzyme by another molecule

Interference at the enzyme-level, basically with how the enzyme works. This can be competitive inhibition, uncompetitive inhibition, non-competitive inhibition or partially competitive inhibition.

Enzyme inhibition and inhibition of metabolismLeads to drug accumulation and toxicity