Drug distribution genetic polymorphisms

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... 

Genetic polymorphism in drug metabolism. The graph shows the distribution of plasma concentrations of isoniazid in 267 individuals 6 hours after an oral dose of 9.8 mg/kg. This distribution is clearly bimodal. Individuals with a plasma concentration greater than 2.5 mg/mL at 6 hours are considered slow acetylators. (Redrawn, with permission, from Evans DAP, Manley KA, McKusick VA Genetic control of isoniazid metabolism in man. Br Med J 1960 2 485.)... 

Disposition in the Body. Readily absorbed after oral administration and widely distributed throughout the body bioavailability 75 to 95%. The major metabolite, V-acetylprocainamide (ace-cainide), has similar pharmacological activity to procainamide the acetylation of procainamide is subject to genetic polymorphism. Up to about 80% of a dose is excreted in the urine of normal subjects in 24 hours, about 50 to 60% as unchanged drug and up to about 30% as V-acetylprocainamide (less in slow acetylators). Other metabolites include monodesethylprocainamide and monodesethyl-V-acetylprocainamide. 

OATP5A1 has been identified, but little is known about its biochemical, physiological, and pharmacological charaderistics. Further studies are required to determine the impact of this transporter on the drug distribution and elimination as well as the consequences of genetic polymorphism (Table 3.2) [106]. 

Studies on identical and non-identical twins have shown that much interindividual pharmacokinetic variability is determined genetically. Pharmacokinetic variability may be caused by genetic polymorphism (the situation where several functionally distinct genes are common in a population) in genes involved in drug absorption, distribution and elimination. In recent years, several polymorphisms in genes encoding for transporter proteins have been described. These polymorphisms could alter the absorption, distribution and elimination of compounds that are substrates for these transporters. However, much work remains to be done to understand the clinical implications of these polymorphisms. 

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