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

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ClinicalTrials.gov Identifier: NCT00187681

Recruitment Status : Completed

First Posted : September 16, 2005

Results First Posted : January 8, 2013

Last Update Posted : January 8, 2013

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Sponsor:

Information provided by (Responsible Party):

University of California, San Francisco

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Other Conditions That May Be A Focus of Clinical Attention	Drug: Metformin	Phase 4

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Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	20 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Official Title:	Effect of Genetic Variants in the Xenobiotic Transporter, OCT1, on Response to Metformin in Healthy Subjects
Study Start Date :	July 2003
Actual Primary Completion Date :	March 2008
Actual Study Completion Date :	March 2008

Resource links provided by the National Library of Medicine

Drug Information available for: Metformin Metformin hydrochloride

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: OCT1-variant Group Subjects with OCT1-variant alleles will be dosed with 2 doses of Metformin	Drug: Metformin 2 doses of Metformin Day 1 1000mg, Day 2 850 mg Other Names: Dimethylguanylguanidine Glucophage
Experimental: OCT1-reference Group Subjects with OCT1-reference alleles will be dosed with 2 doses of Metformin	Drug: Metformin 2 doses of Metformin Day 1 1000mg, Day 2 850 mg Other Names: Dimethylguanylguanidine Glucophage

Outcome Measures

Primary Outcome Measures :

Area Under the Curve (AUC) of Blood Concentration-time of Metformin [ Time Frame: 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours ]
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.
Glucose Lowering Response to Metformin [ Time Frame: 0 to 180 minutes ]
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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 40 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00187681

Locations

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United States, California
San Francisco General Hospital
San Francsico, California, United States, 94143

Sponsors and Collaborators

University of California, San Francisco

Investigators

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Principal Investigator:	Kathleen M Giacomini, PhD	University of California, San Francisco

More Information

Publications of Results:

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. doi: 10.1172/JCI30558.

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. doi: 10.1038/sj.clpt.6100275. Epub 2007 Jul 4.

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Responsible Party:	University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT00187681
Other Study ID Numbers:	865
First Posted:	September 16, 2005 Key Record Dates
Results First Posted:	January 8, 2013
Last Update Posted:	January 8, 2013
Last Verified:	December 2012

Keywords provided by University of California, San Francisco:


Healthy controls

Additional relevant MeSH terms:

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Metformin Hypoglycemic Agents Physiological Effects of Drugs

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