Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187681
Status:
COMPLETED
Last Update Posted:
2013-01-08
First Post:
2005-09-13
Brief Title:
Organic Cation Transporter 1 OCT1 on Response to Metformin in Healthy Subjects
Sponsor:
University of California San Francisco
Organization:
University of California San Francisco
Study Overview
Official Title:
Effect of Genetic Variants in the Xenobiotic Transporter OCT1 on Response to Metformin in Healthy Subjects
Status:
COMPLETED
Status Verified Date:
2012-12
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 Objectives
To determine if individuals who carry a decreased or non-functional variant of OCT1 exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele
To determine if individuals who carry the decreased or non-functional variants exhibit differences in the response to metformin in comparison to individuals who carry the common allele
To determine if individuals who carry a decreased or non-functional variant of OCT1 exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele
To determine if individuals who carry the decreased or non-functional variants exhibit differences in the response to metformin in comparison to individuals who carry the common allele
Detailed Description:
In the proposed studies we will address two questions
Do individuals who carry one of OCT1 variants with reduced or no function exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele
Compared to wild type mice Oct1-- mice have reduced metformin distribution to the liver and intestine We expect a similar pattern between persons who carry the variant OCT1 allele and those who carry the common allele This effect might be reflected by a difference of Tmax or Cmax after oral administration of metformin Other differences in metformin pharmacokinetic properties such as volume of distribution half life and clearance may also be evident
Do individuals who carry the decreased or non-functional variants exhibit differences in the response to metformin in comparison to individuals who carry the common allele Specially we will test the hypothesis that the OCT1-expressing tissues are target organs for metformin and that individuals with the variant transporters may have reduced metformin uptake into these sites is this the correct meaning and therefore a reduced drug response to metformin
In this study we will evaluate metformin pharmacokinetics and glucose metabolic effects in healthy subjects rather than in patients with type 2 diabetes Our rationale is as follows The hepatic glucose production in diabetic patients is abnormally increased Metformin decreases fasting blood glucose concentration by reducing hepatic glucose production and improving glucose utilization However the fasting blood glucose concentration is not decreased by metformin in non-diabetics who have a normal hepatic glucose production It was suggested that the glucose-lowering effect of metformin was difficult to demonstrate in non-diabetics unless glucose concentrations were artificially raised Although there are studies showing that metformin improves the glucose tolerance both in non-diabetics and diabetics the results for non-diabetics have been inconsistent depending on the variable experimental condition Variation in OCT1 expression and activity may be one of those variables and the time points for blood sampling after drug and glucose meal intakes may also be important to observe the glucose-lowering effect 16 In this study we employ a similar study design as that reported 16 to observe the glucose-lowering effect by metformin in healthy subjects Before and after metformin administration oral glucose tolerance test OGTT will be conducted We expect a difference of glucose tolerance between different OCT1 genotypes under the hypothesis that individuals with different OCT1 genotypes have different metformin concentrations in the target tissues and hence have different glucose uptakes into and so utilization in the target tissues primary muscle and liver
In non-diabetic healthy subjects metformin significantly attenuated the rise in immediate postprandial insulin levels In this study we will also determine insulin levels after glucose administration With metformin treatment we expect to observe significant difference in post-glucose-administration insulin levels between individuals with different OCT1 genotypes
When mice were given metformin the blood lactate concentration significantly increased in the wild-type mice whereas only a slight increase was observed in Oct1-- mice This is consistent with our hypothesis that OCT1 is a determinant of metformin effect on glucose utilization It will be interesting to compare plasma lactate concentrations after metformin treatment between individuals with different OCT1 genotypes
Metformin can improve lipid metabolism in obese and diabetics patients which is reflected by the reduced plasma levels of free fatty acid cholesterol and triglycerides However in this study with a single dose of metformin it may not be possible to observe those effects in healthy subjects although the corresponding concentrations will be measured
Do individuals who carry one of OCT1 variants with reduced or no function exhibit differences in the pharmacokinetics of metformin in comparison to individuals who carry the common allele
Compared to wild type mice Oct1-- mice have reduced metformin distribution to the liver and intestine We expect a similar pattern between persons who carry the variant OCT1 allele and those who carry the common allele This effect might be reflected by a difference of Tmax or Cmax after oral administration of metformin Other differences in metformin pharmacokinetic properties such as volume of distribution half life and clearance may also be evident
Do individuals who carry the decreased or non-functional variants exhibit differences in the response to metformin in comparison to individuals who carry the common allele Specially we will test the hypothesis that the OCT1-expressing tissues are target organs for metformin and that individuals with the variant transporters may have reduced metformin uptake into these sites is this the correct meaning and therefore a reduced drug response to metformin
In this study we will evaluate metformin pharmacokinetics and glucose metabolic effects in healthy subjects rather than in patients with type 2 diabetes Our rationale is as follows The hepatic glucose production in diabetic patients is abnormally increased Metformin decreases fasting blood glucose concentration by reducing hepatic glucose production and improving glucose utilization However the fasting blood glucose concentration is not decreased by metformin in non-diabetics who have a normal hepatic glucose production It was suggested that the glucose-lowering effect of metformin was difficult to demonstrate in non-diabetics unless glucose concentrations were artificially raised Although there are studies showing that metformin improves the glucose tolerance both in non-diabetics and diabetics the results for non-diabetics have been inconsistent depending on the variable experimental condition Variation in OCT1 expression and activity may be one of those variables and the time points for blood sampling after drug and glucose meal intakes may also be important to observe the glucose-lowering effect 16 In this study we employ a similar study design as that reported 16 to observe the glucose-lowering effect by metformin in healthy subjects Before and after metformin administration oral glucose tolerance test OGTT will be conducted We expect a difference of glucose tolerance between different OCT1 genotypes under the hypothesis that individuals with different OCT1 genotypes have different metformin concentrations in the target tissues and hence have different glucose uptakes into and so utilization in the target tissues primary muscle and liver
In non-diabetic healthy subjects metformin significantly attenuated the rise in immediate postprandial insulin levels In this study we will also determine insulin levels after glucose administration With metformin treatment we expect to observe significant difference in post-glucose-administration insulin levels between individuals with different OCT1 genotypes
When mice were given metformin the blood lactate concentration significantly increased in the wild-type mice whereas only a slight increase was observed in Oct1-- mice This is consistent with our hypothesis that OCT1 is a determinant of metformin effect on glucose utilization It will be interesting to compare plasma lactate concentrations after metformin treatment between individuals with different OCT1 genotypes
Metformin can improve lipid metabolism in obese and diabetics patients which is reflected by the reduced plasma levels of free fatty acid cholesterol and triglycerides However in this study with a single dose of metformin it may not be possible to observe those effects in healthy subjects although the corresponding concentrations will be measured
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