Genetic Basis for Variation in the Renal Elimination 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. 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. |
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| Condition | Other Conditions That May Be A Focus of Clinical Attention |
| Intervention | Drug: Metformin |
| Phase | Phase 4 |
| Sponsor | University of California, San Francisco |
| 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 |
Tracking Information[ + expand ][ + ]
| First Received Date | September 13, 2005 |
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| Last Updated Date | December 6, 2012 |
| Start Date | May 2002 |
| Estimated Primary Completion Date | April 2008 |
| Current 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. |
| Current Secondary Outcome Measures | Not Provided |
Descriptive Information[ + expand ][ + ]
| Brief Title | Genetic Basis for Variation in the Renal Elimination of Metformin |
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| Official Title | Genetic Basis for Variation in the Renal Elimination 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. 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. |
| 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 Type | Interventional |
| Study Phase | Phase 4 |
| Study Design | Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label |
| Condition | Other Conditions That May Be A Focus of Clinical Attention |
| Intervention | Drug: Metformin Subjects will be given a single oral dose of 850 mg of metformin Other Names: GLUCOPHAGE |
| Study Arm (s) |
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Recruitment Information[ + expand ][ + ]
| Recruitment Status | Completed |
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| Estimated Enrollment | 23 |
| Estimated Completion Date | April 2008 |
| Estimated Primary Completion Date | April 2008 |
| Eligibility 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 |
| Gender | Both |
| Ages | 18 Years |
| Accepts Healthy Volunteers | Accepts Healthy Volunteers |
| Contacts | Not Provided |
| Location Countries | United States |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT00187720 |
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| Other Study ID Numbers | 787 |
| Has Data Monitoring Committee | Yes |
| Information Provided By | University of California, San Francisco |
| Study Sponsor | University of California, San Francisco |
| Collaborators | Not Provided |
| Investigators | Principal Investigator: Kathleen M Giacomini, PhD University of California, San Francsico |
| Verification Date | December 2012 |
Locations[ + expand ][ + ]
| San Francisco General Hospital | San Francisco, California, United States, 94143 |
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