Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1′‐hydroxylation

ABSTRACT:17␣-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC 50 Reports continue to appear describing drug interactions involving oral contraceptive (OC) formulations containing 17␣-ethinyl estradiol (EE). For example, Hilli et al. (2008) reported recently that melatonin (MEL) area under the plasma concentration versus time curve (AUC) is increased (ϳ5-fold), and the 6-hydroxy melatonin (MEL 6-OH)/ MEL AUC ratio is decreased (88%). CYP1A2 is known to play a major role in the metabolism of MEL in human liver microsomes (HLM), so the authors deduced that the enzyme was the locus of the interaction (Facciolá et al., 2001;Härtter et al., 2001;Ma et al., 2005). EE-containing OCs exert a similar effect on the pharmacokinetics (PK) of tizanidine (Granfors et al., 2005). Both tizanidine and MEL are low oral bioavailability (Ͻ25%) CYP1A2 substrates because of first-pass metabolism (Härtter et al., 2001;Granfors et al., 2005). Although caffeine and theophylline also serve as CYP1A2 substrates, they undergo minimal first pass, are highly bioavailable, and the impact of EE is less marked (ϳ40% decrease in clearance) (Roberts et al., 1983;Balogh et al., 1995). Despite these clinical data, it is only very recently that assessment of CYP1A2 inhibition in vitro has been described previously (Karjalainen et al., 2008). In fact, Karjalainen et al. (2008) reported EE as a relatively weak inhibitor of phenacetin O-deethylation (POD) activity in HLM (low K m component; IC 50 ϭ 24 M).Drug interactions with EE-containing OC formulations have also included a number of CYP2C19 substrates, such as omeprazole, mephenytoin, and proguanil (Hägg et al., 2001; Rodrigues and Lu, 2004, references therein;Shelepova et al., 2005). Likewise, drug interactions with imipramine and selegiline have been described previously (Abernethy et al., 1984;Laine et al., 1999). The latter is a CYP2B6 and CYP2C19 substrate, also with a low oral bioavailability (Ͻ10%), and greater than 10-fold increases in AUC have been reported with OCs (Laine et al., 1999;Benetton et al., 2007). More importantly, the contribution of CYP2C19 after oral dosing of selegiline is thought to be minimal (Laine et al., 2001). Although CYP2B6 is implicated, there are no reports describing the impact of CYP2B6 genotype (or phenotype) on the oral PK of selegiline, and its contribution in vivo is not known. Moreover, the clinical drug interaction between EE and a CYP2B6 probe (bupropion) is not significant despite evidence for mechanism-based inhibition in vitro Palovaara et al., 2003). The same can also be said for the observed mechanism-based inhibition of CYP3A4 and CYP3A5 in vitro because the effect of EE on the PK of CYP3A substrates (e.g., midazolam and nifedipine) is minimal (Balogh et al., 1998; Article, publication date, and citation information c...

Section: Discussionsupporting

confidence: 68%

mentioning

confidence: 81%

Further Assessment of 17α-Ethinyl Estradiol as an Inhibitor of Different Human Cytochrome P450 Forms in Vitro

Chang¹,

Chen²,

Yang³

et al. 2009

“…Although they are CYP3A inhibitors, they were located here because they inhibit CYP3A directly, not in a metabolism-based manner. Ethynylestradiol, which is located in zone 2, is a potent metabolism-based inhibitor, but it does not cause in vivo DDI because of its usually low blood concentrations of Յ1 nM dmd.aspetjournals.org (Kuhnz et al, 1996;Palovaara et al, 2000). Compounds reported to cause both MBI and significant in vivo DDIs, such as diltiazem, verapamil, clarithromycin, erythromycin, mibefradil, and nefazodone, were mainly located in zone 3.…”

Section: Discussionmentioning

confidence: 99%

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Watanabe

Nakamura²,

Okudaira³

et al. 2007

ABSTRACT:The CYP3A family is a major drug metabolism enzyme in humans. Metabolism-based inhibition of CYP3A might cause clinically significant drug-drug interactions (DDIs). To assess the risk of DDIs caused by metabolism-based inhibition (MBI) of CYP3A, we established an automated single time-and concentration-dependent inhibition assay. To create a diagram to assess DDI risk of compounds in the early discovery stage, we classified 171 marketed drugs by the possibility of the occurrence of in vivo DDI caused by MBI from the relationship between the inactivation activity determined in the MBI screening, the therapeutic blood or plasma concentration, and the in vivo DDI information. This analysis revealed that the DDI risk depends on both the MBI potential and the blood concentration of a compound, and provided the criteria of the DDI risk. In the assay, three compounds (midazolam, nifedipine, and testosterone) were compared as CYP3A probe substrates. The results show that the evaluation for MBI does not depend on the probe substrates used in the assay. In addition, we established an automated assay to distinguish quasi-irreversible and irreversible binding to CYP3A in which the quasi-irreversible inhibitors such as diltiazem, verapamil, and nicardipine were dissociated from CYP3A by the addition of potassium ferricyanide, whereas the irreversible inhibitors such as clozapine, delavirdine, and mibefradil were not. It provides useful information related to chemical structures likely to cause MBI. By using these MBI assays supported by an extensive database of marketed compounds, a systematic MBI evaluation paradigm was established and has been incorporated into our drug discovery process.The cytochrome P450 (P450) superfamily comprises many isozymes that metabolize xenobiotic chemicals, including drugs (Guengerich, 2001). CYP1A2, 2C9, 2C19, 2D6, and 3A participate in the metabolism of approximately 80% of therapeutic drugs, such that the majority of P450-mediated drug metabolism is mediated by the CYP3A family (Wienkers and Heath, 2005). CYP3A4 is a major isoform of CYP3A. It has been reported that CYP3A5 may also contribute to the metabolism of CYP3A4 substrates because of the overlapping substrate specificity with CYP3A4 . Drugs metabolized by P450s may also inhibit the metabolism of coadministered drugs, which results in an increased blood concentration of the coadministered drugs (Bertz and Granneman, 1997). As a result, a patient to whom two or more drugs are administered might suffer from adverse effects induced by such a drug-drug interaction (DDI). Drugs such as terfenadine, mibefradil, cisapride, and nefazodone have been withdrawn from the market because of P450-related DDIs (Wienkers and Heath, 2005). Consequently, pharmaceutical companies now investigate the P450 inhibitory potential of drug candidates in the early stage of development (Wienkers and Heath, 2005). P450 inhibition can be classified into three categories: reversible, quasi-irreversible, and irreversible inhibition (Murray, 1997;Lin and Lu,...

“…Based on our preliminary data, therefore, the k inact /K I ratio of EE for CYP2C19 is probably lower than that for CYP3A4 (0.002 min Ϫ1 ⅐ M Ϫ1 ). 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 4Ј-hydroxylase activity.…”

mentioning

confidence: 99%

IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

Rodrigues¹,

Lü²

2004

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 (ϳ100%) 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 (K i ϳ100 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 (IC 50 ϭ 19 M) of CYP2C19 (4Ј-hydroxylation of (S)-mephenytoin) in human liver microsomes. The IC 50 was determined at the...