Effect of Genetic Variants in the Xenobiotic Transporter, OCT1, on Response to Metformin in Healthy Subjects

In the proposed studies, we will address two questions:

•Do individuals who carry one of OCT1 variants with reduced or no function exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele?

Compared to wild type mice, Oct1-/- mice have reduced metformin distribution to the liver and intestine. We expect a similar pattern between persons who carry the variant OCT1 allele and those who carry the common allele. This effect might be reflected by a difference of Tmax or Cmax after oral administration of metformin. Other differences in metformin pharmacokinetic properties such as volume of distribution, half life and clearance may also be evident.

•Do individuals who carry the decreased or non-functional variants exhibit differences in the response to metformin in comparison to individuals who carry the common allele? Specially, we will test the hypothesis that the OCT1-expressing tissues are target organs for metformin, and that individuals with the variant transporters may have reduced metformin uptake into these sites (is this the correct meaning?) and therefore a reduced drug response to metformin.

In this study, we will evaluate metformin pharmacokinetics and glucose metabolic effects in healthy subjects rather than in patients with type 2 diabetes. Our rationale is as follows. The hepatic glucose production in diabetic patients is abnormally increased. Metformin decreases fasting blood glucose concentration by reducing hepatic glucose production and improving glucose utilization. However, the fasting blood glucose concentration is not decreased by metformin in non-diabetics who have a normal hepatic glucose production. It was suggested that the glucose-lowering effect of metformin was difficult to demonstrate in non-diabetics unless glucose concentrations were artificially raised. Although there are studies showing that metformin improves the glucose tolerance both in non-diabetics and diabetics, the results for non-diabetics have been inconsistent, depending on the variable experimental condition. Variation in OCT1 expression and activity may be one of those variables, and the time points for blood sampling after drug and glucose (meal) intakes may also be important to observe the glucose-lowering effect [16]. In this study, we employ a similar study design as that reported [16] to observe the glucose-lowering effect by metformin in healthy subjects. Before and after metformin administration, oral glucose tolerance test (OGTT) will be conducted. We expect a difference of glucose tolerance between different OCT1 genotypes, under the hypothesis that individuals with different OCT1 genotypes have different metformin concentrations in the target tissues, and hence have different glucose uptakes into (and so utilization in) the target tissues (primary muscle and liver).