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

Abstract

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...

Pharmacotherapy for Mood Disorders in Pregnancy

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