Effect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the PKPD of Metformin (#6112)

Effect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the Pharmacokinetics and Pharmacodynamics of Metformin

The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. The investigators will study individuals with particular genotypes of the human organic cation transporter, (hOCT2), and the multidrug and toxin extrusion transporters, MATE1, MATE2-K to test the hypothesis that genetic variation in hOCT2, hMATEE1 and hMATE2-K are associated with variation in the pharmacokinetics and/or pharmacodynamics of the antidiabetic agent, metformin.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Metformin

Detailed Description

In the proposed study, a genotype to phenotype strategy is employed to study the role of the transporters, OCT2, MATE1, and MATE2-K and related variants in response and disposition to a known substrate, metformin. Recently, one polymorphic variant in MATE1 (PMT4302, g.-66T>C) showed decreased promoter activity by 40-45% (p<0.01), and one MATE2-K variant (PMT5597, g.-130G>A) showed increased promoter activity by 30% (p<0.05), compared to the reference. Both are the most common promoter variants in each gene (the frequencies of PMT4302: 32.1% and 23.1% in Caucasian and Asian; PMT5597: 26.2% and 48.5% in Caucasian and Asian) (unpublished data, Giacomini group). Specifically, the investigators will measure renal clearance of metformin, and plasma glucose and insulin levels, in healthy Caucasian and Asian subjects who carry either the reference or variant alleles in order to evaluate the effects of these variants on metformin disposition and response.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects self-identify racial background, identify themselves, parents and four grandparents as Caucasian and or Chinese.
• Subject status is healthy volunteer from the SOPHIE cohort
• Subjects over 18 years old
• Subjects who are healthy on the basis of medical history, physical examinations and laboratory tests if healthy volunteer from SOPHIE
• Subjects who agree with the written informed consent to participate in the study.

Exclusion Criteria:

• Under 18 years old
• Pregnant or lactating woman (female subjects will have a urine pregnancy test at the Day 1 visit)
• They report a prior history of any allergic reaction to metformin
• Has a risk of congestive heart failure requiring pharmacologic treatment (medical history)
• Has a prior history of renal* or hepatic dysfunction (renal and hepatic function will be evaluated based on screening blood tests conducted prior to study enrollment)
• Anemic (screening lab values, hemoglobin <10 g)
• Taking a medication that could confound study results (such as known substrates or inhibitors of OCT2, MATE1 and MATE2-K such as cimetidine)
• Subjects are undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function
• They do not consent to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Metformin; Subjects will be given an oral dose of metformin once per day for two days.	Drug: Metformin; Subjects will be given an oral dose of metformin once per day for two days.; Other Names: GLUCOPHAGE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal clearance of Metformin based on genotypes	Renal clearance of Metformin of study participants using reference genotype for transporters of OCT2, MATE1, and MATE2-K. In addition, Cmax for plasma glucose will be analyzed for all study participants.	Study day procedures 48 hours

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 1, 2012
• First Submitted That Met QC Criteria: September 5, 2012
• First Posted (Estimate): September 10, 2012

Study Record Updates

• Last Update Posted (Estimate): July 2, 2014
• Last Update Submitted That Met QC Criteria: June 30, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 6112 (Other Identifier: Stanford IRB)