Abstract
Objectives
The hypoglycaemic drug tolbutamide is used for assessment of CYP2C9 activity in vivo. However, therapeutically active doses of 500 mg bear the risk of hypoglycaemia, and a tolbutamide-derived parameter based on a single plasma or urine concentration reflecting CYP2C9 activity accurately is lacking.
Methods
We examined tolbutamide and its metabolites 4′-hydroxy-tolbutamide and carboxytolbutamide in plasma and urine of 26 healthy, male volunteers up to 24 h after intake of 125 mg tolbutamide using liquid chromatography–tandem mass spectrometry. CYP2C9 genotypes were determined by sequencing of exons 3 and 7. Raw plasma and urine data were compared with pharmacokinetic parameters, CYP2C9 genotypes, and data from a study in 23 volunteers with all six CYP2C9*1–*3 combinations who received 500 mg tolbutamide.
Results
Plasma clearance and tolbutamide plasma concentrations 24 h after drug intake reflected the genotypes: 0.85 l/h and 1.70 µg/ml (95% confidence interval, CI, 0.80–0.89 l/h and 1.50–1.90 µg/ml) for CYP2C9*1 homozygotes (n=15), 0.77 l/h and 2.14 µg/ml (95%CI, 0.67–0.88 l/h and 1.64–2.63 µg/ml) for *1/*2 genotypes (n=7), 0.60 l/h and 3.13 µg/ml (95%CI, 0.58–0.62 l/h and 2.68–3.58 µg/ml) for *1/*3 genotypes (n=3), and 0.57 l/h and 3.27 µg/ml in the single *2/*2 carrier. Natural logarithms of tolbutamide plasma concentrations 24 h after intake correlated to plasma clearance (r2=0.84, P<0.0000001). This correlation was confirmed in the comparison data set (r2=0.97, P<0.0000001).
Conclusions
A low dose of 125 mg tolbutamide can safely and accurately be used for CYP2C9 phenotyping. As a simple metric for CYP2C9 activity, we propose to determine tolbutamide in plasma 24 h after drug intake.
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Acknowledgements
We like to express our thanks to Hendrik Lück and Dirk Kroll for the excellent study organisation and to Anke Rattay for skilful technical assistance. Grants of Bayer AG, Wuppertal, Germany, and Novartis, Basel, Switzerland, were obtained for parts of the study A.
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Jetter, A., Kinzig-Schippers, M., Skott, A. et al. Cytochrome P 450 2C9 phenotyping using low-dose tolbutamide. Eur J Clin Pharmacol 60, 165–171 (2004). https://doi.org/10.1007/s00228-004-0754-z
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DOI: https://doi.org/10.1007/s00228-004-0754-z