Genetic Basis for Variation in the Renal Elimination of Metformin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00187720
First received: September 13, 2005
Last updated: December 6, 2012
Last verified: December 2012
  Purpose

The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. We will study individuals with particular genotypes of the human organic cation transporter, (hOCT2), to test the hypothesis that genetic variation in hOCT2 is associated with variation in the renal clearance of the antidiabetic agent, metformin.


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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Genetic Basis for Variation in the Renal Elimination of Metformin

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Renal Clearance of Metformin [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours ] [ Designated as safety issue: No ]
    To test whether individuals with genetic variants of the human organic cation transporter, OCT2, exhibit altered renal elimination of metformin we will measure the difference in renal clearance between reference and variant groups.


Enrollment: 23
Study Start Date: May 2002
Study Completion Date: April 2008
Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OCT2-variant Group
Subjects with OCT2-variant genotype will be given a single oral dose of 850 mg of metformin.
Drug: Metformin
Subjects will be given a single oral dose of 850 mg of metformin
Other Name: GLUCOPHAGE
Experimental: OCT2-reference Group
Subjects with OCT2-reference genotype will be given a single oral dose of 850 mg of metformin.
Drug: Metformin
Subjects will be given a single oral dose of 850 mg of metformin
Other Name: GLUCOPHAGE

Detailed Description:

The drug, which is used in the treatment of Type II diabetes, has a narrow therapeutic range. Its net renal clearance by secretion (i.e., renal clearance minus filtration clearance) ranges from approximately 100 ml/min to 800ml/min in normal, healthy subjects. Although many factors may contribute to inter-individual variation in renal secretory clearance, initial estimates of heritability (greater than 0.6) suggest that genetic factors play an important role in the renal secretion of metformin. Available evidence supports the idea that hOCT2 is the primary transporter involved in the first-step of renal secretion of metformin, i.e., uptake from the blood to the tubule cell across the basolateral membrane. In particular, (a) hOCT2 is the primary organic cation transporter on the basolateral membrane of the human kidney; and (b) metformin interacts with and is translocated by hOCT2 in heterologous expression systems.

In recent studies, we identified four variants (M165I, A270S, R400C, and K432Q) with ethnic-specific allele frequencies ≥1% [6] that have altered function in studies in heterologous expression systems. In addition, we identified a common haplotype of hOCT2 and one haplotype that contain the non-synonymous cSNP, A270S. We will determine whether variability in the renal secretory clearance of the model organic cation, metformin, in healthy individuals is associated with genetic variation in hOCT2. In particular, we will determine whether the renal clearance of metformin differs in individuals who are homozygous for the common haplotype of OCT2 (OCT2*1) and those who are heterozygous for the less common haplotype OCT2*3D, which we have identified in a comprehensive screen of ethnically identified DNA samples. We will also determine whether individuals who are heterozygous for the less common OCT2 variants, M165I, R400C and K432Q, have reduced renal clearances of metformin.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects have previously participated in the Study Of Pharmacogenetics In Ethnically Diverse Populations (SOPHIE) study.
  • 18-40 years old
  • Possess a pre-specified genotype for OCT2

Exclusion Criteria:

  • Taking any regular 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 or breastfeeding
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00187720

Locations
United States, California
San Francisco General Hospital
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Kathleen M Giacomini, PhD University of California, San Francsico
  More Information

Publications:
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00187720     History of Changes
Other Study ID Numbers: 787
Study First Received: September 13, 2005
Results First Received: March 31, 2011
Last Updated: December 6, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
Healthy Control

Additional relevant MeSH terms:
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 15, 2014