Drug Metabolism and ProdrugsDrug Metabolism and Prodrugs

Drug metabolism is the transformation of foreign compounds ( xenobiotics) into water soluble derivatives which can easily eliminate via renal route.

XenobioticsXenobiotics

( non essential exogenous, foreign compounds )

• This applies particularly to chemical compounds which enter the organism and don't serve as nutrient or other essential factors.

• Xenobiotics can not be allowed to concentrate beyond limits in a living system, but must be eliminate by excretion. Xenobiotics metabolism

appears as a logical evolutionary acquisition.

• Drug metabolism may be regarded as detoxification processes in some cases.

• Not all metabolites are non toxic

ExampleExample

As a rule, the metabolism of xenobiotics As a rule, the metabolism of xenobiotics takes place in two steps known as phase I & takes place in two steps known as phase I & phase II reactionsphase II reactions

Phase I ( functionalization reaction )Phase I ( functionalization reaction )

New polar groups such COOH, OH, SO3H or NH2 are introduced or unveiled from pre-existing function through oxidative, reductive

or hydrolytic reactions.

Phase II ( conjugation reactions )Phase II ( conjugation reactions )

• Link an endogenous solubilizing moiety either to the original drug (if polar function are already present) or to the phase I metabolite.

• Common solubilizing groups are glucuronic acid, various amino acids or sulphate grops.

• The conjugate molecule, being more polar and water-soluble, is usually excreted via the renal route

Effect of metabolism on the therapeutic Effect of metabolism on the therapeutic activity of drugsactivity of drugs

ConclusionConclusion • Drug metabolism or biotransformation are the

chemical reactions that are responsible for the conversion of drugs into other products within the body before and after they have reached their sites of action.

• Almost all of these reactions are enzyme catalyzed. • A knowledge of the concepts of drug metabolism is

useful in both the design of new drugs and the improvement of existing drugs.

Factors affecting drug metabolismFactors affecting drug metabolism

• Genetic factors

• Physiological factors

• Pharmaceutical factors

• Drug interactions

Genetic factorsGenetic factors

Biological half –life (t1/2) of various drugs

Physiological factorsPhysiological factors

Pharmacodynamic factorsPharmacodynamic factors

• The dose, the route and the frequency of administration of drugs can affect their metabolic profiles.

• Drugs given too frequently may overload the metabolic system available to it, leading to elevated blood and tissue levels of the drugs. The effect of protein binding also influences the metabolism

Drug interactionsDrug interactions• Phenobarbital stimulate the metabolism of

Diphenylhydantoin.

• The half life of Chloropropamide, Diphenylhydantoin & Cyclophosphamide is increase in presence of Chloramphenicol.

• Plasma Concentration of anticoagulants such as Warfarin are reduced by simultaneous application of barbiturate

Phase I (Functionalization reactionsPhase I (Functionalization reactions

• Oxidations (electron removal, dehydrogenation and hydroxylation)

• Reduction ( electron donation, hydrogenation

and removal of oxygen )

• Hydrolytic reactions

Oxidation ReactionsOxidation Reactions

• The main enzymes involved in the oxidation of xenobiotics called mixed – function oxidases or monooxygenases, found mainly in the liver but also occur to less extent in other tissues.

• Cytochrom P-450 ( CYP – 450 )

Simplified Cytochrome P450 Redox Cycle

Major reactions of oxygenation catalyzed by Major reactions of oxygenation catalyzed by cytochrome P450cytochrome P450

Major reactions of oxygenation catalyzed by Major reactions of oxygenation catalyzed by cytochrome P450cytochrome P450

Oxidation reactionsOxidation reactions

1. Carbon oxidation reaction

a - Hydroxylation of saturated aliphatic carbon atoms b - Hydroxylation at activated SP3 carbon atoms c - Oxidation attack on unsaturated aliphatic systems d - Hydroxylation of aromatic rings

2. N-oxygenation reactions

3. S-oxidation reactions

Hydroxylation of saturated aliphatic Hydroxylation of saturated aliphatic carbon atomscarbon atoms

• Saturated aliphatic C-H bonds are normally metabolised by hydroxylation ( ω & ω-1 )

Enzymatic introduction of a hydroxyl group into Enzymatic introduction of a hydroxyl group into cyclohexane ring generally occurs at C-3 or C-4cyclohexane ring generally occurs at C-3 or C-4

In human the trans-4-hydroxycyclohexyl product has been reported as a major metabolite of acetohexamide ( hypoglycemic agent )

TerodilineAromatic p-hydroxylation predominate with R-

isomer where as benzylic hydroxylation is preferred with S-isomer.

Hydroxylation at activated SPHydroxylation at activated SP3 3 carbon atomscarbon atoms

Oxidation involving carbo-heteroatom Oxidation involving carbo-heteroatom systemsystem

N-dealkylationN-dealkylation

Halogenated aliphatic derivativesHalogenated aliphatic derivatives

Oxidation attack on unsaturated Oxidation attack on unsaturated aliphatic systemsaliphatic systems