Abstract
Objective
The hydroxylation of omeprazole, measured as the ratio of omeprazole/5-hydroxyomeprazole in a plasma sample taken 3 h after an oral dose, is an established method to determine CYP2C19 activity, and the ratio of omeprazole AUC/omeprazole sulfone AUC has been used for assessing CYP3A4 activity. The aim of this study was to determine whether the latter ratio from a single 3-h sample can also be used for CYP3A4 phenotyping.
Methods
Plasma levels of omeprazole and omeprazole sulfone were analyzed by reversed-phase high-performance liquid chromatography in a blood sample drawn 3 h after intake of a single oral 20-mg dose of omeprazole by 22 healthy subjects and five patients with newly diagnosed epilepsy. The procedure was repeated on the 4th day of 200 mg of ketoconazole intake (10 subjects), after 3 weeks of 150–200 mg twice-daily carbamazepine (five patients), and on the 6th day of 4 mg twice-daily tolterodine (12 subjects). Five subjects also took 100 mg and 50 mg of ketoconazole for 3 days before concomitant intake with omeprazole.
Results
The mean log10(omeprazole/omeprazole sulfone) ratio was 0.18 3 h after intake of omeprazole alone. After concomitant intake of ketoconazole, the corresponding value was 1.38 (p<0.001); after intake of carbamazepine it was −0.42 (p<0.05); and after tolterodine it was 0.29 (not significant). In the five subjects taking increasing doses of ketoconazole, the ratio was 0.11, 0.79, 1.2, and 1.5 after 0, 50, 100, and 200 mg of ketoconazole, respectively. The correlation between the metabolic ratios from the AUC(0-6h) and from the single 3-h samples was very good, with a correlation coefficient of 0.92 (p<0.001).
Conclusions
A single blood sample taken 3 h after intake of 20 mg of omeprazole can be reliably used to phenotype for both CYP2C19 and CYP3A4 activity.
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References
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN (1999) Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokin 37(6):485–505
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270(1):414–423
Walan A (1989) Clinical experience with omeprazole: assessment of efficacy and safety. J Gastroenterol Hepatol 4(Suppl 2):27–33
Andersson T, Regardh CG, Dahl-Puustinen ML, Bertilsson L (1990) Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 12(4):415–416
Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L (1995) Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5(6):358–363
Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Tassaneeyakul W, Meyer UA et al (1993) Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 36:521–530
Böttiger Y (2000) Metabolic drug interactions in man—methodological aspects on in vivo studies. Dissertation, Karolinska Institutet, Stockholm
Böttiger Y, Tybring G, Gotharson E, Bertilsson L (1997) Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 62(4):384–391
Bertilsson L, Tybring G, Widen J, Chang M, Tomson T (1997) Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol 44(2):186–189
Brynne N, Bottiger Y, Hallen B, Bertilsson L (1999) Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol 47(2):145–150
Christensen M, Andersson K, Dalén P, Mirghani RA, Muirhead GJ, Nordmark A et al (2003) The Karolinska cocktail for phenotyping of five cytochrome P450 enzymes. Clin Pharmacol Ther 73(6):517–528
Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM et al (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin [published erratum appears in Clin Pharmacol Ther 55(6):648]. Clin Pharmacol Ther 51(4):388–397
Rost KL, Roots I (1996) Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. Hepatology 23(6):1491–1497
Tybring G, Bottiger Y, Widen J, Bertilsson L (1997) Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 62(2):129–137
Gonzalez HM, Romero EM, Aaron Peregrina A, Chavez TJ, Escobar-Islas E, Lozano F, et al (2003) CYP2C19- and CYP3A4-dependent omeprazole metabolism in West Mexicans. J Clin Pharmacol 43:1211–1215
Acknowledgements
All coauthors of the previously published studies who have contributed data to the present study are warmly acknowledged for their thorough scientific work: L. Bertilsson, G. Tybring, J. Widén, M. Chang, T. Tomson, N. Brynne, B. Hallen, and E. Götharson. This study was supported by a grant from the National Network for Drug Development, within the Foundation for Strategic Research, Sweden.
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Financial support was obtained from the National Network for Drug Development, within the Foundation for Strategic Research, Sweden.
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Böttiger, Y. Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4. Eur J Clin Pharmacol 62, 621–625 (2006). https://doi.org/10.1007/s00228-006-0156-5
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DOI: https://doi.org/10.1007/s00228-006-0156-5