Organic Cation Transporter 1 (OCT1), on Response to Metformin in Healthy Subjects

Other Conditions That May Be A Focus of Clinical Attention Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00187681
• Other study ID #: 865
• Status: Completed
• Phase: Phase 4
• First received: September 13, 2005
• Last updated: December 6, 2012
• Start date: July 2003
• Est. completion date: March 2008

Study information

• Verified date: December 2012
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Specific Objectives:

• To determine if individuals who carry a decreased or non-functional variant of OCT1 exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele.

• To determine if 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.

Description:

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).

In non-diabetic healthy subjects, metformin significantly attenuated the rise in immediate postprandial insulin levels. In this study, we will also determine insulin levels after glucose administration. With metformin treatment, we expect to observe significant difference in post-glucose-administration insulin levels between individuals with different OCT1 genotypes.

When mice were given metformin, the blood lactate concentration significantly increased in the wild-type mice, whereas only a slight increase was observed in Oct1-/- mice. This is consistent with our hypothesis that OCT1 is a determinant of metformin effect on glucose utilization. It will be interesting to compare plasma lactate concentrations after metformin treatment between individuals with different OCT1 genotypes.

Metformin can improve lipid metabolism in obese and diabetics patients, which is reflected by the reduced plasma levels of free fatty acid, cholesterol, and triglycerides. However, in this study with a single dose of metformin, it may not be possible to observe those effects in healthy subjects, although the corresponding concentrations will be measured.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 2008
• Est. primary completion date: March 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Previous participation in the Study Of Pharmacogenetics In Ethnically Diverse Populations (SOPHIE) study.

• Between the ages of 18 and 40.

• Possess a specific OCT1 genotype.

Exclusion Criteria:

• Taking any medications other than vitamins

• Individuals with anemia (hemoglobin < 12 g/dL), an elevation in liver enzymes to higher than double the respective normal value, or elevated creatinine concentrations (males = 1.5 mg/dL, females = 1.4 mg/dL)

• Pregnant at time of study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Other Conditions That May Be A Focus of Clinical Attention

Intervention

Drug:
• Metformin
2 doses of Metformin Day 1 1000mg, Day 2 850 mg

Locations

Country	Name	City	State
United States	San Francisco General Hospital	San Francsico	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (2)

Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008 Feb;83(2):273-80. — View Citation

Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007 May;117(5):1422-31 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Curve (AUC) of Blood Concentration-time of Metformin	To test whether individuals with genetic variants of human organic cation transporter, OCT1, exhibit altered pharmacokinetics of metformin, the difference in AUC of blood concentration-time of metformin between reference and variant groups will be measured.	0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours	No
Primary	Glucose Lowering Response to Metformin	To test whether individuals with genetic variants of human organic cation transporter, OCT1, exhibit altered glucose lowering response to metformin we will measure the difference in area under the glucose concentrations-time curve (Glucose AUC) following oral glucose tolerance test.	0 to 180 minutes	No