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- Title
Cytochrome P<sub>450</sub> 2C9 phenotyping using low-dose tolbutamide.
- Authors
Jetter, Alexander; Kinzig-Schippers, Martina; Skott, Andreas; Lazar, Andreas; Tornalik-Scharte, Dorota; Kirchheiner, Julia; Walchner-Bonjean, Monika; Hering, Ursula; Jakob, Verena; Rodamer, Michael; Jabrane, Wafaâ; Kasel, Dirk; Brockmöller, Jürgen; Fuhr, Uwe; Sörgel, Fritz
- 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.
- Subjects
TOLBUTAMIDE; HYPOGLYCEMIC agents; PHARMACODYNAMICS; BLOOD plasma; CHROMATOGRAPHIC analysis; BODY fluids
- Publication
European Journal of Clinical Pharmacology, 2004, Vol 60, Issue 3, p165
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-004-0754-z