BIOTRANSFORMATION DEFINITION Chemical alteration of a drugchemical inside

BIOTRANSFORMATION

DEFINITION • Chemical alteration of a drug/chemical inside our body is called as biotransformation/metabolism

Why Biotransformation? • • • Most drugs are excreted by the kidneys • For renal excretion drugs should: – have small molecular mass – be polar in nature – not be fully ionized at body p. H Most drugs are complex and do not have these properties and thus have to be broken down to simpler products.

Why Biotransformation? Drugs are lipophilic in nature • Thus readily pass across biological barriers • Strongly bound to plasma proteins • This property also stops them from getting eliminated They have to be converted to simpler hydrophilic compounds so that they are eliminated and their action is terminated.

Where Do Drug Biotransformations Occur? • The liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the • gastrointestinal tract, • lungs, • skin, • kidneys.

Who is carrying out Drug Biotransformations? • Although drug biotransformation in vivo can occur by spontaneous, non-catalyzed chemical reactions, the vast majority of transformations are catalyzed by specific cellular enzymes. • At the sub cellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.

Drug metabolizing enzymes • Cytochrome P 450 (CYP 450) is the major drug metabolizing enzyme system in the body. • Also known as “mixed function monooxygenases” • Liver and gut wall have the greatest concentration of P 450 • Almost all tissues in the body have some P 450 (Lungs, Kidney, Skin, Brain, etc)

CYP Isoforms • CYP 1 A 2, 2 A 6, 2 C 9, 2 D 6, 2 E 1, and 3 A 4 appear to be the major forms that carry out metabolic reactions. CYP 450 Isoform DRUG SUBSTRATE 1 A 2 Theophylline , warfarin 2 A 6 Coumarine 2 C 9 Ibuprofen , phenytoin 2 D 6 Haloperidol, tricyclic antidepressants 2 E 1 Halothane , ethanol 3 A 4 Acetaminophen, progesteroneterfenadine, testosterone,

CYP Isoforms % DRUGS METABOLIZED BY CYP ENZYMES

Biotransformation : Consequences 1. Active drug Inactivation morphine 6 -hydroxy morphine 2. Active drug Active metabolite digitoxin digoxin 3. Inactive drug(prodrug) Active drug L-dopamine Enalaprilat Bacampicillin

Phases • Biotransformation reactions can be: – Phase I reactions – Phase II reactions

Phase I reactions Catabolic in nature – e. g. Oxidation, Reduction, Hydrolysis End-products are chemically more reactive Metabolites are usually more polar than the parent drug. • Introduce a reactive group – ie functional group • The functional group becomes the starting point for Phase II reaction. • •

Phase I reactions • Cytochrome P 450 is the major enzyme system (Oxidations, reductions, etc. ) Phase I metabolites may be: • Inactive • Equally Active • More Active • Toxic • Activated - “prodrug” • Polar metabolites may be excreted.

Phase I reactions Reaction example 1. Oxidation Warfarin , morphine 2. Reduction Halothane, chloramphenicol 3. Hydroysis Lignocaine, procaine 4. Cyclization Proguanil 5. Decyclization Phenytoin, barbiturates

Phase II reactions • Synthetic processes • If a drug is not rendered to hydrophilic molecule by Phase-I reactions, Phase –II is required. • An endogenous substrate is coupled to an existing (or phase I formed) conjugation site. • Forms a highly polar conjugate • Phase II reactions usually occur after Phase I but can also take place earlier than Phase I

Phase II reactions Type of Conjugation Examples Glucuronidation Morphine, acetaminophen, diazepam Acetylation Sulfonamides, isoniazid Glutathione conjugation Ethacrynic acid Glycine conjugation Salicylic acid, benzoic acid, nicotinic acid Sulfate conjugation acetaminophen, methyldopa Methylation Dopamine, epinephrine Water conjugation Carbamazepine, Leukotriene A 4

Drug molecule I More hydrophilic metabolite II Conjugate Bile Kidney Intestines Urine Feces De-conjugation and reuptake (entero-hepatic cycling)

Enzyme Induction • Reversible increase in enzyme concentration • Resulting from administration of certain drugs • May increase the metabolism of other drugs taken concurrently Consequences: • Decreased duration of action of an active drug due to fast inactivation. • Increased intensity of action of an inactive drug due to fast activation

Enzyme Induction Inducer Drug whose metabolism is enhanced Griseofulvin Warfarin Barbiturates Phenytoin, testosterone, estradiol, digoxin Phenytoin OCPs, Theophylline Rifampin OCPs, coumarin anticoagulants, propranolol

Enzyme Inhibition • Some drugs can block P 450 enzymes that metabolise other drugs • Unlike induction, enzyme inhibition usually begins with the first dose of the inhibitor. Consequences: • May increase serum concentrations of second drug • Can lead to toxicity

Enzyme Inhibition Inhibitor Drug whose metabolism is Inhibited Cimetidine Warfarin Disulfiram Ethanol Ketoconazole Terfenadine Grape Fruit Juice Alprazolam, cisapride