TY - JOUR T1 - Further Assessment of 17α-Ethinyl Estradiol as an Inhibitor of Different Human Cytochrome P450 Forms in Vitro JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1667 LP - 1675 DO - 10.1124/dmd.109.026997 VL - 37 IS - 8 AU - Shu-Ying Chang AU - Cliff Chen AU - Zheng Yang AU - A. David Rodrigues Y1 - 2009/08/01 UR - http://dmd.aspetjournals.org/content/37/8/1667.abstract N2 - 17α-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 IC50 (concentration of inhibitor required to decrease activity by 50%) values were obtained with recombinant CYP1A1 (rCYP1A1) [IC50(total) = IC50(free) = 2.7 μM] and CYP2C19 activity in human liver microsomes (HLM) [IC50(total) = 4.4 μM; IC50(free) = 2.8 μM]. For rCYP1A1, formal inhibition studies revealed that EE was a competitive inhibitor [Ki(free) = 1.4 μM]. All the other IC50 values were greater than 8.0 μM, and the weakest inhibition was observed with CYP1A2 activity in HLM (IC50(free) > 39 μM). In agreement, the IC50 characterizing the inhibition of melatonin (MEL) 6-hydroxylation in human intestine microsomes (CYP1A1-catalyzed) was lower than that of HLM (0.91 versus >40 μM). Because EE is known to affect the pharmacokinetics of CYP2C19 probe drugs, this result raises the possibility that the concentration of EE during first pass may exceed 1000 nM, sufficient to affect CYP1A1 and CYP2C19, with less impact on CYP3A4 and other P450s. The results implicate intestinal CYP1A1, and possibly CYP2C19, as the loci of EE drug interactions with highly extracted drugs like MEL. Overall, it is very difficult to rationalize drug interactions involving EE based on direct inhibition of CYP2B6 (e.g., selegiline) and hepatic CYP1A2 (e.g., MEL, tizanidine, caffeine, and theophylline). ER -