Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187798
Status:
COMPLETED
Last Update Posted:
2012-09-25
First Post:
2005-09-13
Brief Title:
Impact of Genetics on Metformin Pharmacokinetics
Sponsor:
University of California San Francisco
Organization:
University of California San Francisco
Study Overview
Official Title:
Impact of Genetics on Metformin Pharmacokinetics
Status:
COMPLETED
Status Verified Date:
2012-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 1960s and 1970s 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 P450s 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 15 to 42 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
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 15 to 42 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None