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These isoenzymes are a major determinant of the pharmacokinetic behavior of numerous …
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- Cytochrome P450 enzyme isoforms and their therapeutic implications: An update
Biotransformation or metabolism of drugs leads to chemical alteration of the drug in the body. It is needed to render non polar (lipid soluble) compounds polar (lipid insoluble) so that they are not reabsorbed in the kidney tubules and are excreted. Biotransformation reactions can be classified as either Phase 1 functionalization reactions or Phase 2 biosynthetic (conjugation) reactions. Phase 1 reactions introduce or expose a functional group (-OH, -NH 2 , -SH) on the parent compound, metabolite formed are inactive but in some instances active metabolites are also formed. Phase 1 reactions generally lead to loss of pharmacological activity e.g., morphine, propanolol, pentobarbitone etc. Prodrugs (pharmacologically inactive compounds but after metabolism have active metabolite) gets bioactivated after phase 1 reactions e.g., levodopa, enalapril etc.
Phase 2 conjugation reactions lead to the formation of a covalent linkage between a functional group on the parent compound or phase 1 metabolite with endogenously derived glucuronic acid, sulfate, glutathione, amino acids or acetate. These highly polar conjugates are generally inactive and are excreted rapidly in urine and feces. The enzyme involved in phase 1 reactions are located primarily in endoplasmic reticulum, while the phase 2 conjugation enzyme systems are primarily cytosolic.
Metabolites can alter the pharmacological action of drug qualitatively. Terfenadine, a non sedating antihistaminic, can, rarely cause serious cardiac dysrythmias by blocking cardiac potassium channels whereas its pharmacologically active metabolite (fexofenadine) blocks histamine H 1 receptors but not cardiac potassium channels and it has replaced terfenadine. The selective serotonin reuptake inhibitors (SSRIs) like fluoxetine is demethylated to norfluoxetine which is pharmacologically active and has a elimination half life of 10 days as compared to parent compound which is just 50 hrs. Norfluoxetine also competes with other agents for hepatic oxidases to elevate plasma concentrations of other agents, including tricyclic antidepressants, days after administration of the parent drug has been stopped.
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