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Cytochrome P450 2C9 phenotyping using low-dose tolbutamide.
Alexander Jetter1, Martina Kinzig-Schippers, Andreas Skott
1Department of Pharmacology, Clinical Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany. alexander.jetter@medizin.uni-koeln.de
European Journal of Clinical Pharmacology
|March 27, 2004
Summary
A low dose of 125 mg tolbutamide can safely assess CYP2C9 activity. Measuring tolbutamide plasma levels 24 hours post-dose provides a reliable metric for CYP2C9 phenotyping.
Area of Science:
- Pharmacology
- Genetics
- Biochemistry
Background:
- Tolbutamide is a hypoglycemic drug used to assess CYP2C9 activity in vivo.
- Therapeutic doses (500 mg) pose a risk of hypoglycemia.
- A reliable method for CYP2C9 phenotyping using tolbutamide is needed.
Purpose of the Study:
- To evaluate the safety and accuracy of a lower tolbutamide dose (125 mg) for CYP2C9 phenotyping.
- To establish a simple metric for assessing CYP2C9 activity based on plasma tolbutamide concentrations.
Main Methods:
- 26 healthy male volunteers received 125 mg tolbutamide.
- Plasma and urine concentrations of tolbutamide and its metabolites were measured up to 24 hours post-dose using LC-MS/MS.
- CYP2C9 genotypes were determined via sequencing.
Main Results:
- Plasma clearance and 24-hour plasma tolbutamide concentrations correlated with CYP2C9 genotypes.
- A strong correlation was observed between the natural logarithm of 24-hour plasma tolbutamide concentrations and plasma clearance (r²=0.84).
- This correlation was validated in a separate dataset (r²=0.97).
Conclusions:
- A 125 mg dose of tolbutamide is safe and effective for CYP2C9 phenotyping.
- Measuring plasma tolbutamide 24 hours after administration is a proposed simple metric for CYP2C9 activity.