Pharmacokinetic Control Based on Pharmacogenetic Information for Drug Transportersand Its Application to Optimizing Drug Therapy

Abstract

Although passive diffusion, which depends on the lipid solubility, has been believed to be an exclusive mechanism for the membrane transport of many compounds, we have demonstrated that several drugs are transported into or out from the cells by the tissue-specific transporters in intestinal and renal epithelial cells, hepatocytes and brain capillary endothelial cells which form the blood-brain barrier. During these studies, we found the genetic polymorphism in drug transporters, using organic cation/carnitine transporter OCTN2. Only from the volunteers that showed low carnitine blood concentration, several kinds of heterozygous mutations of OCTN2 gene that show functional loss were found. Furthermore, based on the phenotype observed by systemic carnitine deficiency, many types of mutations in OCTN2 were found with functional loss for carnitine and several organic cations. Accordingly, organic cations that are transported by OCTN2 are suggested to have altered pharmacokinetic behavior in the people who have an allele heterozygously. This is the first demonstration of genetic polymorphism in organic cation transporters found in normal population. Such pharmacogenomic study is a rapidly emerging field focused on understanding the genetic factors underlying individual pharmacokinetics of drugs among patients and applying this information to improve the clinical use and development of pharmaceutical products.