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0090-9556/04/3203-364–365$20.00 DRUG METABOLISM AND DISPOSITION Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics DMD 32:364–365, 2004 Vol. 32, No. 3 1326/1128823 Printed in U.S.A. Letter to the Editor IS 17␣-ETHINYL ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19? 1 Abbreviations used are: OC, oral contraceptive; EE, 17␣-ethinyl estradiol; LNG, levonorgestrel; PK, pharmacokinetics; S/R ratio, ratio of (S)-mephenytoin to (R)-mephenytoin in urine. trol. Therefore, these data imply that the concentration of inhibitor/Ki ratio for EE is very low. EE has been shown to be a mechanism-based inhibitor (KI, 18 M; kinact, 0.04 min⫺1) of CYP3A4 in vitro (Lin et al., 2002). In our hands, up to 70% inhibition of testosterone 6-hydroxylase activity was observed when EE (50 M) was preincubated (30 min) with NADPHfortified human liver microsomes. In contrast, preincubation of EE (0.1 to 50 M) with human liver microsomes resulted in no inhibition of (S)-mephenytoin 4⬘-hydroxylase activity. Ticlopidine (10 M), on the other hand, behaved as a preincubation time-dependent inhibitor (50% inhibition) and also served as a positive control (Tateishi et al., 1999; Ko et al., 2000; Ha-Duong et al., 2001). Based on our preliminary data, therefore, the kinact/KI ratio of EE for CYP2C19 is probably lower than that for CYP3A4 (0.002 min⫺1 䡠 M⫺1). It is worth noting that despite overt mechanism-based inhibition of CYP3A4 in vitro, EE has a modest effect on the PK and metabolism of midazolam, a sensitive CYP3A4 probe drug (Palovaara et al., 2000; Belle et al., 2002; Lin et al., 2002). The in vitro study described herein was expanded to include a number of EE metabolites (e.g., EE 3-O-sulfate, EE 3-O-glucuronide, and 2-methoxy EE), and none were shown to be inhibitors of human liver microsomal (S)-mephenytoin 4⬘-hydroxylase activity. At first glance, it is difficult to conclude that the effect of OCs on CYP2C19 activity is due to inhibition (reversible or mechanismbased) of the enzyme by EE. Further studies are needed to elucidate the mechanism of interaction involving omeprazole and mephenytoin. Toward this end, it will be important to evaluate carefully the estrogenic and progestogenic components of OC formulations and their metabolites, as reversible and mechanism-based inhibitors of CYP2C19 in vitro. In turn, in vitro-in vivo correlations can be attempted. Such studies are important because it has been estimated that up to 70 million women worldwide take OC formulations (Belle et al., 2002), and relatively little mechanistic information is available concerning the effects of these formulations on cytochromes P450. Department of Drug Metabolism, Merck Research Laboratories, West Point, PA A. DAVID RODRIGUES2 PING LU References Abelo A, Andersson TB, Antonsson M, Naudot AK, Skanberg I, and Weidolf L (2000) Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 28:966 –972. Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, and Shader RI (1982) Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids. N Engl J Med 306:791–792. Belle DJ, Callaghan JT, Gorski JC, Maya JF, Mousa O, Wrighton SA, and Hall SD (2002) The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. Br J Clin Pharmacol 53:67–74. Chang M, Tybring G, Dahl M-L, Gotharson E, Sagar M, Seensalu R, and Bertilsson L (1995) Inter-phenotype differences in disposition and effect on gastrin levels of omeprazole: suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol 39:511–518. Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, and Mansuy D (2001) Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry 40:12112–12122. Hagg S, Spigset O, and Dahlqvist R (2001) Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 51:169 –173. Hidestrand M, Oscarson M, Salonen JS, Nyman L, Pelkonen O, Turpeinen M, and Ingelman2 Present address: Drug Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ. 364 Downloaded from dmd.aspetjournals.org at ASPET Journals on October 28, 2016 We have read with great interest the increasing number of publications reporting that oral contraceptive (OC)1 formulations can decrease CYP2C19 activity. For example, Palovaara et al. (2003) evaluated the effect of two OC formulations on the hydroxylation of omeprazole. One formulation contained EE (40 g) and LNG (60 g), whereas the second contained LNG (60 g) and was devoid of EE. The combination of EE and LNG increased both the area under the plasma concentration vs. time curve of omeprazole (38%) and the omeprazole to 5-hydroxy omeprazole area under the plasma concentration vs. time curve ratio (48%). LNG alone had no affect on the PK and metabolism of omeprazole. In addition, neither formulation inhibited CYP3A4-catalyzed omeprazole sulfone formation. Because the hydroxylation of omeprazole is widely accepted as an index of CYP2C19 activity (Chang et al., 1995; Lasker et al., 1998; Abelo et al., 2000; Kita et al., 2001), the authors concluded that OC preparations containing EE decrease CYP2C19 activity. The observations of Palovaara et al. (2003) confirm the findings of Laine et al. (2000), who also reported an increase (⬃100%) in the omeprazole to 5-hydroxy omeprazole ratio in plasma. In the same study, the ratio of (S)-mephenytoin to (R)-mephenytoin in urine (S/R ratio) increased from 0.11 to 0.28, and the effect was similar to that observed with subjects genotyped CYP2C19*1/*2 (versus CYP2C19*1/*1). A comparable change in the S/R ratio has been reported by Hagg et al. (2001) and Tamminga et al. (1999). EE-containing OC formulations have also been shown to affect the PK and metabolism of diazepam, propranolol, proguanil, and selegiline (Abernethy et al., 1982; Walle et al., 1996; Laine et al., 1999; McGready et al., 2003). All four drugs are reported to be CYP2C19 substrates. However, the effect of EE on their PK cannot be ascribed to CYP2C19 alone, because other cytochromes P450 are involved in metabolism (Jung et al., 1997; Yang et al., 1999; McGinnity et al., 2000; Hidestrand et al., 2001). The same cannot be said for the urinary mephenytoin S/R ratio and the omeprazole to 5-hydroxy omeprazole ratio in plasma. Both have served as a useful index of CYP2C19 activity and have been validated with genotyped subjects (Rodrigues and Rushmore, 2002). Although the results of these various clinical drug interaction studies are compelling, it cannot be assumed that EE is a clinically relevant inhibitor of CYP2C19. The dose of EE is low (30 –50 g), and peak plasma concentrations (total EE) range between 0.6 and 0.7 nM (Belle et al., 2002). Moreover, Jurima et al. (1985) have reported that EE itself is a weak inhibitor (Ki ⬃100 M) of human liver microsomal mephenytoin (racemate) hydroxylase activity, whereas Laine et al. (2003) observed inhibition (70%) of omeprazole 5-hydroxylation only at a high concentration of EE (0.1 mM). We have also determined that EE is a relatively weak, reversible inhibitor (IC50 ⫽ 19 M) of CYP2C19 (4⬘-hydroxylation of (S)-mephenytoin) in human liver microsomes. The IC50 was determined at the Km of (S)-mephenytoin (80 M; substrate concentration/Km ⬃1.0) and (R)N-3-benzyl-phenobarbital (IC50 ⫽ 0.3 M) served as a positive con- LETTER TO THE EDITOR McGinnity DF, Parker AJ, Soars M, and Riley RJ (2000) Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s. Drug Metab Dispos 28:1327–1334. McGready R, Stepniewska K, Seaton E, Cho T, Cho D, Ginsberg A, Edstein MD, Ashley E, Looareesuwan S, White NJ, and Nosten F (2003) Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharmacol 59:553–557. Palovaara S, Kivisto KT, Tapanainen P, Manninen P, Neuvonen PJ, and Laine K (2000) Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1⬘-hydroxylation. Br J Clin Pharmacol 50:333–337. Palovaara S, Tybring G, and Laine K (2003) The effect of ethinylestradiol and levonorgestrel on CYP2C19-mediated metabolism of omeprazole in healthy female subjects. Br J Clin Pharmacol 56:232–237. Rodrigues AD and Rushmore TH (2002) Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences. Curr Drug Metab 3:289 –309. Tamminga WJ, Wemer J, Oosterhuis B, Wieling J, Wilffert B, de Leij LFMH, De Zeeuw RA, and Jonkman JHG (1999) CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol 55:177–184. Tateishi T, Kumai T, Watanabe M, Nakura H, Tanaka M, and Kobayashi S (1999) Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism. Br J Clin Pharmacol 47:454 – 457. Walle T, Fagan TC, Walle UK, and Topmiller MJ (1996) Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women. Br J Clin Pharmacol 41:305–309. Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, and Gelboin HV (1999) Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos 27:102–109. Downloaded from dmd.aspetjournals.org at ASPET Journals on October 28, 2016 Sundberg M (2001) CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson’s disease, as revealed from experiments with recombinant enzymes. Drug Metab Dispos 29:1480 –1484. Jung F, Richardson TH, Raucy JL, and Johnson EF (1997) Diazepam metabolism by cDNAexpressed human 2C P450s: identification of P4502C18 and P4502C19 as low KM diazepam N-demethylases. Drug Metab Dispos 25:133–139. Jurima M, Inaba T, and Kalow W (1985) Mephenytoin hydroxylase activity in human liver: inhibition by steroids. Drug Metab Dispos 13:746 –749. Kita T, Tanigawara Y, Aoyama N, Hohda T, Saijoh Y, Komada F, Sakaeda T, Okumura K, Sakai T, and Kasuga M (2001) CYP2C19 genotype related effect of omeprazole on intragastric pH and antimicrobial stability. Pharm Res (NY) 14:615– 621. Ko JW, Zeruesenay D, Soukhova NV, Tracy T, and Flockhart DA (2000) In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 49:343–351. Laine K, Anttila M, Helminen A, Karnani H, and Huupponen R (1999) Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids. Br J Clin Pharmacol 47:249 –254. Laine K, Tybring G, and Bertilsson L (2000) No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 68:151–159. Laine K, Yasar U, Widen J, and Tybring G (2003) A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes. Pharmacol Toxicol 93:77– 81. Lasker JM, Wester MR, Aramsombatdee E, and Raucy JL (1998) Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsome tolbutamide, S-mephenytoin and omeprazole hydroxylations. Arch Biochem Biophys 353:16 –28. Lin HL, Kent UM, and Hollenberg PF (2002) Mechanism-based inactivation of cytochrome P450 3A4 by 17␣-ethynylestradiol: evidence for heme destruction and covalent binding to protein. J Pharmacol Exp Ther 301:160 –167. 365