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Genetic Basis for Variation in the Renal Elimination of Metformin

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ClinicalTrials.gov Identifier: NCT00187720
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : January 10, 2013
Last Update Posted : January 10, 2013
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

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

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Official Title: Genetic Basis for Variation in the Renal Elimination of Metformin
Study Start Date : May 2002
Actual Primary Completion Date : April 2008
Actual Study Completion Date : April 2008

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Arms and Interventions
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Arm Intervention/treatment
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


Outcome Measures
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Primary Outcome Measures :
  1. Renal Clearance of Metformin [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours ]
    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.


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:

  • 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
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Information from the National Library of Medicine

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): NCT00187720


Locations
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United States, California
San Francisco General Hospital
San Francisco, 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 Francsico
More Information
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Publications of Results:

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00187720    
Other Study ID Numbers: 787
First Posted: September 16, 2005    Key Record Dates
Results First Posted: January 10, 2013
Last Update Posted: January 10, 2013
Last Verified: December 2012
Keywords provided by University of California, San Francisco:
Healthy Control
Additional relevant MeSH terms:
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Metformin
Hypoglycemic Agents
Physiological Effects of Drugs