2001 Volume 16 Issue 2 Pages 127-133
In the present study, we examined the genetic polymorphism in drug transporters, using organic cation/carnitine transporter OCTN2 as a model transporter. Since OCTN2 plays a role in carnitine transport by mediating especially a renal reabsorption of carnitine from urine, free carnitine concentrations in blood and urine were used for phenotyping of the genetic mutation of OCTN2. From general population (n=973), the phenotyping resulted in 46 people with significantly low blood free carnitine concentration. Among them 36 people and 69 normal people were further examined for their free carnitine concentration and OCTN2 genes. Only from the group that showed a low carnitine blood concentration, three kinds of heterozygous mutations of OCTN2 gene that show functional loss were found. Furthermore, based on the phenotype observed by systemic carnitine deficiency patients and their family, many type of mutations in OCTN2 were found with functional loss. So, phenotyping of OCTN2 gene by blood and urinary concentration of carnitine is a efficient way to identify the polymorphism of OCTN2 that shows functional alteration. Since OCTN2 was suggested to be involved in renal excretion of organic cations such as tetraethylammonium, genetic polymorphisms that cause functional alteration in carnitine transport may change the pharmacokinetics of organic cations. However, the OCTN2-mediated transport mechanism in carnitine transport is different from that of organic cations in terms of sodium ion dependency, the functional alterations of carnitine transport activity by genetic polymorphism are not necessarily cause the same effect on the pharmacokinetics of organic cations. In addition to OCTN2, we found genetic polymorphism in organic anion transporter OATP-C, which is an important transporter for hepatic excretion of anionic drugs in human. So, we need further functional analysis of various alleles of transporter genes for the better understanding of inter-individual differences of pharmacokinetic characteristics of drugs.
