Ziritaxestat Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition
In vitro signals indicate that ziritaxestat is really a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with dental contraceptives were examined at any given time when ziritaxestat was under development to treat fibrotic illnesses. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who have been using impressive contraception, like a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence. Just one dose of dental contraceptive (.03 mg ethinyl estradiol (EE) and three mg drospirenone (DRSP)) was administered on days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from days 8 to 23. Co-administration led to a couple.8-fold and a pair of.4-fold rise in EE maximum plasma concentration (Cmax ) and area underneath the plasma drug concentration-time curve from time zero to infinity (AUC0-inf ), correspondingly (day 18 versus. first day). DRSP Cmax and AUC0-inf elevated by 1.1-fold and 1.2-fold, correspondingly. DRSP is really a CYP3A4 substrate, meaning elevated EE exposure with ziritaxestat wasn’t because of CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by liquid chromatography with tandem mass spectrometry in first day and day 18 plasma samples after EE conjugate hydrolysis. The number of EE AUC from duration of administration to the duration of the final quantifiable concentration (AUClast ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 versus. first day, suggesting ziritaxestat is really a potent inhibitor of sulfation EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is really a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 µM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.