Tolbutamide is known to be metabolized by cytochrome P450 2C9 (CYP2C9), and the effects of the CYP2C9 amino acid polymorphisms *2 (Arg144Cys) and *3 (Ile359Leu) could be important for drug treatment with tolbutamide and for use of tolbutamide as a CYP2C9 test drug. Tolbutamide pharmacokinetics and plasma insulin and glucose concentrations were studied in 23 healthy volunteers with all six combinations of the CYP2C9 alleles *1, *2 and *3, including two subjects with the combined CYP2C9*1/*1 and CYP2C19*2/*2 genotype. Volunteers received a single oral dose of 500 mg tolbutamide, followed by 75 g oral glucose at 1, 4.5 and 8 h after tolbutamide administration. Pharmacokinetic analysis was performed using a computer program for regression analysis of nonlinear mixed effects models. The mean oral clearances of tolbutamide were 0.97 (95% confidence interval [CI] 0.89-1.05), 0.86 (95% CI 0.79-0.93), 0.75 (95% CI 0.69-0.81), 0.56 (95% CI 0.51-0.61), 0.45 (95% CI 0.41-0.49) and 0.15 (95% CI 0.14-0.16) l/h in carriers of CYP2C9 genotypes 1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3, respectively. Tolbutamide pharmacokinetics in carriers of the functionally deficient CYP2C19*2/*2 genotype were not different from those in the CYP2C19 highly active genotype. Elimination in the six CYP2C9 genotype groups could be expressed as the linear combination of three constants (0.05, 0.04, 0.01 h(-1), which were specific to the respective CYP2C9 alleles *1, *2 and *3, thus indicating a co-dominant mode of inheritance. Insulin and glucose concentration-time curves did not change with differing CYP2C9 genotypes. Tolbutamide was confirmed as a substrate of the genetically polymorphic enzyme CYP2C9. The pronounced differences in pharmacokinetics due to the amino acid variants did not significantly affect plasma insulin and glucose concentrations in healthy volunteers.

Nonlinear kinetics of omeprazole and its metabolites bacter pylori. 2,6 Thus far, omeprazole kinetics were were investigated after treatment with repeated high studied upon single doses of 10 to 80 mg [7][8][9][10][11] Two major primary metabolites, omeprazole sulfone that CYP2C19-dependent plasma clearance of omepra-and 5 -hydroxyomeprazole, are formed by cytochromes zole and omeprazole sulfone was reduced from 19.0 to P450 3A (CYP3A) and 2C19 (CYP2C19), respectively 8.4 L/h (P õ .001) and from 19.8 to 9.2 L/h (P Å .012), (Fig. 1). Both metabolites undergo further metabolism respectively. Similarly, formation half-life of 5 -hydroxy-to the common metabolite 5 -hydroxyomeprazole sulomeprazole increased from 0.58 to 1.45 hours (P Å .025) fone via CYP2C19 and CYP3A, respectively. 14-16 Thus, with the higher dose. CYP3A-dependent metabolic both CYP enzymes are sequentially-but alternaroutes remained unaffected. Thus, high-dose treatment tively-involved in omeprazole metabolism. CYP2C19, the area under the plasma concentration-time curve (AUC) of omeprazole 8,10,17,18 in comparison with extenThe irreversible H / , K / -adenosine triphosphatase in-sive metabolizers (EMs). The latter represent 96 to 97% hibitor omeprazole is successfully used in various gas-of a Caucasian, but only about 80% of a Far Eastern tric acid-related disorders. It is a generally well-toler-population. 19,20 A hereditary deficiency of the alternaated drug, even in long-term treatment. 1,2 Changes in tive enzyme, CYP3A, has not been shown. gastrointestinal cell structure and function remain lim-The clinical necessity to apply high omeprazole doses ited. 3 Clinical doses range from 20 to 40 mg/d for the may create concerns of exceedingly high omeprazole treatment of gastric and duodenal ulcers, 20 to 80 mg/d concentrations that may result from nonlinear (saturafor reflux esophagitis, and 20 to 120 mg/d for Zollinger-tion) kinetics. Moreover, in PMs, elimination of omeEllison syndrome 2-5 or in the eradication of Helico-prazole is confined to CYP3A activity. Especially in those genetically defined patients, omeprazole elimination might be impaired drastically, if CYP3A activity is inhibited by comedication, e.g., by macrolides such Abbreviations: CYP3A, cytochrome P450 3A; CYP2C19, cytochrome P450 2C19; PMs, poor metabolizers; AUC, area under the plasma concentrationas erythromycin or antifungals such as ketoconazole. 17 time curve; EMs, extensive metabolizers.We evaluated omeprazole plasma kinetics after treat- kinetics of 40 mg once daily in EMs and PMs. MetaboReceived September 25, 1995; accepted February 9, 1996. lite patterns are evaluated to distinguish CYP2C19 and Address reprint requests to Karl Ludwig Rost, M.D., Institut fü r Klinische CYP3A activity with respect to dose linearity.

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