Impact of Genetics on Metformin Pharmacokinetics
Overview[ - collapse ][ - ]
| Purpose | Specific Aims: To compare metformin pharmacokinetics in monozygotic and dizygotic twin pairs. Comparing renal clearance of metformin in monozygotic and dizygotic twins will allow us to better understand the influence of heredity on variation in renal elimination. Furthermore, genotyping renal transporter genes in monozygotic and dizygotic twin pairs with significant differences in renal clearance of metformin may give us insight into the genes responsible for this variability. |
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| Condition | Other Conditions That May Be A Focus of Clinical Attention |
| Intervention | Drug: Metformin HCl |
| Phase | N/A |
| Sponsor | University of California, San Francisco |
| Responsible Party | University of California, San Francisco |
| ClinicalTrials.gov Identifier | NCT00187798 |
| First Received | September 13, 2005 |
| Last Updated | September 24, 2012 |
| Last verified | September 2012 |
Tracking Information[ + expand ][ + ]
| First Received Date | September 13, 2005 |
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| Last Updated Date | September 24, 2012 |
| Start Date | August 2001 |
| Estimated Primary Completion Date | July 2007 |
| Current Primary Outcome Measures | To compare metformin pharmacokinetics in monozygotic and dizygotic twin pairs. [Time Frame: 24 hours] [Designated as safety issue: No]Comparing renal clearance of metformin in monozygotic and dizygotic twins will allow us to better understand the influence of heredity on variation in renal elimination. Furthermore, genotyping renal transporter genes in monozygotic and dizygotic twin pairs with significant differences in renal clearance of metformin may give us insight into the genes responsible for this variability. |
| Current Secondary Outcome Measures | Not Provided |
Descriptive Information[ + expand ][ + ]
| Brief Title | Impact of Genetics on Metformin Pharmacokinetics |
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| Official Title | Impact of Genetics on Metformin Pharmacokinetics |
| Brief Summary | Specific Aims: To compare metformin pharmacokinetics in monozygotic and dizygotic twin pairs. Comparing renal clearance of metformin in monozygotic and dizygotic twins will allow us to better understand the influence of heredity on variation in renal elimination. Furthermore, genotyping renal transporter genes in monozygotic and dizygotic twin pairs with significant differences in renal clearance of metformin may give us insight into the genes responsible for this variability. |
| Detailed Description | Twin studies have long been a valuable tool for examining the relative role of environment and heredity in health issues such as disease and drug response. For example, twin studies in the 1960's and 1970's showed for the first time that variability in the elimination of many drugs was largely influenced by heredity. Monozygotic twin pairs showed little variability in the elimination of various drugs while dizygotic twin pairs, sharing only about one half of their genes, showed much greater variability. It is now known that the some of the variability in drug elimination observed in dizygotic twins was due to genetic differences in drug metabolizing enzymes, such as the cytochrome P450's. However, genetic variation in other genes, such as membrane transporters may also contribute to variability in drug response. Membrane transporters play multiple roles in the body; they help to maintain cellular homeostasis through import and export mechanisms and also play an important role in drug response, affecting both the pharmacokinetics and pharmacodynamics of drugs. Animal studies using mice genetically deficient in drug transporters and reports of drug interaction studies involving transporter substrates have provided convincing evidence that the level of function of several important drug transporters is an important determinant of drug response. The current study will examine differences in the renal clearance of metformin in monozygotic and dizygotic twin pairs. Metformin is an antidiabetic drug that has no significant hepatic metabolism and is actively secreted by the kidneys. Studies in our lab have shown that metformin is a substrate of the human organic cation transporter, hOCT2, which appears to be a major transporter involved in the renal secretion of cationic drugs. Data in the literature indicate that there is substantial variation in the net secretory clearance of metformin in normal, healthy volunteers. In five healthy volunteers, the ratio of renal clearance to creatinine clearance ranged from 1.5 to 4.2, nearly a 3-fold variation. We hypothesize that genetic variation in secretory transporters in the kidney, like hOCT2, may be responsible for the inter-individual differences in the secretory clearance of metformin and other drugs. Studies examining renal clearance of metformin in monozygotic and dizygotic twins will allow us to better understand the influence of heredity on variation in renal elimination. Furthermore, genotyping monozygotic and dizygotic twin pairs with significant differences in renal clearance of metformin may give us insight into the genes responsible for this variability. |
| Study Type | Interventional |
| Study Phase | N/A |
| Study Design | Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic |
| Condition | Other Conditions That May Be A Focus of Clinical Attention |
| Intervention | Drug: Metformin HCl Subjects will be given a single oral dose in tablet form containing 850 mg of metformin Other Names: GLUCOPHAGE |
| Study Arm (s) | Other: Metformin Metformin HCl |
Recruitment Information[ + expand ][ + ]
| Recruitment Status | Completed |
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| Estimated Enrollment | 24 |
| Estimated Completion Date | July 2007 |
| Estimated Primary Completion Date | July 2007 |
| Eligibility Criteria | Inclusion Criteria: - Part of either a monozygotic or dizygotic twin pair. - Healthy (by medical history and laboratory values). - Between 18 and 40 years old. Exclusion Criteria: - Taking regular medication 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 at time of study. - Diagnosis of hypoglycemia, phlebitis and/or stroke will be excluded. |
| Gender | Both |
| Ages | 18 Years |
| Accepts Healthy Volunteers | Accepts Healthy Volunteers |
| Contacts | Not Provided |
| Location Countries | United States |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT00187798 |
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| Other Study ID Numbers | 928 |
| 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 Giacomini, PhD University of California San Francsico |
| Verification Date | September 2012 |
Locations[ + expand ][ + ]
| University of California San Francsico | San Francisco, California, United States, 94143 |
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