Drug metabolism genetic polymorphisms

Plasma elimination t is 6 hours. Voriconazole exhibits nonlinear kinetics, and higher doses disproportionately increase drug exposure. Genetic polymorphisms in CYP2C19 can cause up to a fourfold difference in drug exposure -20% of Asians are poor metabolizers compared to 2% of Caucasians and African Americans. Drug exposure is increased considerably in the elderly and in patients with mild or moderate hepatic insufficiency. Patients with hepatic cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose. 

Many are inhibited by various drugs or their metabolic products, providing another cause of drug interactions Some exhibit genetic polymorphisms, which can result in atypical drug metabolism... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Polymorphic metabolism Genetically determined rates of metabolism (fast vs. slow) by selected isozymes of cytochrome P-450 drug-metabolizing enzymes. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Kapitany, T., Meszaros, K., Lenzinger, E. et al. (1998). Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophr. Schizophr. Res., 32, 101-6. 

Meyer, U.A. (1994a). The molecular basis of genetic polymorphisms of drug metabolism. /. Pharm. Pharmacol, 46(1), 409-15. 

Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 1997 37 269-296. 

Nebert DW. Polymorphisms in drug-metabolizing enzymes what is their clinical relevance and why do they exist Am J Hum Genet 1997 60 265-271. 

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