Phase I and Phase II Reactions of Drug

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Phase I and Phase II Reactions of Drug Metabolism:

By: P.K arthik Kumar, 09BU1R0010, MLR Institute Of Pharmacy. Guided By: Mr. Nikhil Sir, ( Dept. of Pharm. Technology) Phase I and Phase II Reactions of Drug Metabolism

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Phases I and II of the metabolism of a lipophilic drug.

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Phase I Reactions

Phase I Reactions:

Phase I Reactions Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. Phase I can turn a nontoxic molecule into a poisonous one (toxification). Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.

Phase I reactions include::

Phase I reactions include: Oxidation Reduction Hydrolysis

Oxidation:

Oxidation A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen.

Cytochrome P450 monooxygenase system:

Cytochrome P450 monooxygenase system

Reduction:

Reduction NADPH-cytochrome P450 reductase Cytochrome P450 reductase also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase The general scheme of electron flow in the POR/P450 system is: NADPH → FAD → FMN → P450 → O2 Reduced (ferrous) cytochrome P450 During reduction reactions, a chemical can enter futile cycling , in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).

Hydrolysis:

Hydrolysis Simple hydrolysis in the stomach transforms, which are comparatively innocuous. But Phase I metabolism converts acetonitrile to HOCH 2 CN, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic. Hydroxylation of an N-methyl group leads to expulsion of a molecule of formaldehyde, while oxidation of the O-methyl groups takes place to a lesser extent.

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Phase II Reactions

Phase II Reactions:

Phase II Reactions Phase II reactions are usually known as conjugation reactions which are usually detoxicating in nature, and involve the interactions of the polar functional groups of phase I metabolites. Sites on drugs where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH 2 ), and sulfhydryl (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites.

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Mechanism Involved enzyme Co-factor Location Methylation Methyltransferase S-adenosyl-L-methionine Liver, kidney, lung, CNS Sulphation Sulfotransferases 3'-phosphoadenosine-5'-phosphosulfate Liver, kidney, intestine Acetylation N-acetyltransferases Bile acid-CoA:amino acid N-acyltransferases Acetyl coenzyme A Liver, lung, spleen, gastric mucosa, RBCs , lymphocytes Glucuronidation UDP-glucuronosyltransferases UDP-glucuronic acid Liver, kidney, intestine, lung, skin, prostate, brain Glutathione conjugation Glutathione S-transferases Glutathione Liver, kidney Glycine conjugation Acetyl Co-enzyme As Glycine Liver, kidney

References:

References Bernardin Akagah ; Anh Tuan Lormier ; Alain Fournet ; Bruno Figadere (2008). "Oxidation of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite production of drug candidates". Organic & Biomolecular Chemistry 6 (24): 4494–7. http://en.wikipedia.org/wiki/Cytochrome_P450_oxidase Liston, H.; Markowitz, J.; Devane , C. (2001). "Drug glucuronidation in clinical psychopharmacology". Journal of Clinical Psychopharmacology 21 (5): 500–515. "Simulation and prediction of in vivo drug metabolism in human populations from in vitro data". Nature Reviews Drug Discovery 6 (2): 140–8.

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