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

Overview[ - collapse ][ - ]

Purpose 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.
ConditionHealthy
InterventionDrug: Metformin
PhasePhase 4
SponsorUniversity of California, San Francisco
Responsible PartyUniversity of California, San Francisco
ClinicalTrials.gov IdentifierNCT01681680
First ReceivedAugust 1, 2012
Last UpdatedSeptember 5, 2012
Last verifiedSeptember 2012

Tracking Information[ + expand ][ + ]

First Received DateAugust 1, 2012
Last Updated DateSeptember 5, 2012
Start DateOctober 2010
Estimated Primary Completion DateDecember 2012
Current Primary Outcome Measures
  • Renal clearance of the Metformin [Time Frame: 24 hours post-dose] [Designated as safety issue: No]To test whether individuals with genetic variants of transporters, OCT2, MATE1, and MATE2-K, exhibit altered pharmacokinetics of metformin.
  • Plasma glucose [Time Frame: 0, 15, 30, 45, 60, 90, 120, 180 minutes after glucose administration] [Designated as safety issue: No]To test whether individuals with genetic variants of transporters OCT2, MATE1, and MATE2-K, exhibit altered glucose lowering response to metformin.
Current Secondary Outcome MeasuresNot Provided

Descriptive Information[ + expand ][ + ]

Brief TitleEffect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the PKPD of Metformin
Official TitleEffect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the Pharmacokinetics and Pharmacodynamics of Metformin
Brief Summary
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.
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 TypeInterventional
Study PhasePhase 4
Study DesignEndpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
ConditionHealthy
InterventionDrug: Metformin
Subjects will be given an oral dose of metformin once per day for two days.
Other Names:
GLUCOPHAGE
Study Arm (s)Other: Metformin
Subjects will be given an oral dose of metformin once per day for two days.

Recruitment Information[ + expand ][ + ]

Recruitment StatusActive, not recruiting
Estimated Enrollment60
Estimated Completion DateDecember 2012
Estimated Primary Completion DateOctober 2012
Eligibility Criteria
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
GenderBoth
Ages18 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsNot Provided
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01681680
Other Study ID Numbers6112
Has Data Monitoring CommitteeYes
Information Provided ByUniversity of California, San Francisco
Study SponsorUniversity of California, San Francisco
CollaboratorsNot Provided
Investigators Principal Investigator: Kathleen M Giacomini, PhD University of California, San Francisco
Verification DateSeptember 2012

Locations[ + expand ][ + ]

San Francisco General Hospital
San Francisco, California, United States, 94110