Pregnancy related hormones increase CYP3A mediated buprenorphine metabolism in human hepatocytes: a comparison to CYP3A substrates nifedipine and midazolam

Introduction: Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic expression metabolism. However, it remains unclear to what extent magnitude PRH-evoked changes in CYP3A metabolism varies across multiple substrates. This study quantified impact PRHs on protein concentrations buprenorphine human hepatocytes, compared these effects nifedipine midazolam Methods: Sandwich-cultured hepatocytes (SCHH) from female donors were exposed PRHs, administered combination a range physiologically relevant concentrations, for 72 h. Absolute CYP3A4, CYP3A5, CYP3A7 SCHH membrane fractions by nanoLC-MS/MS, norbuprenorphine (nor-BUP), dehydro-nifedipine (dehydro-NIF), 1-hydroxy-midazolam (1-OH-MDZ) formation was evaluated. Results: Compared control, PRH exposure increased CYP3A7, total but not CYP3A5 nor-BUP, dehydro-NIF, 1-OH-MDZ concentration-dependent manner. The each positively correlated with PRH-mediated concentrations. increase nor-BUP evident all donors; however, induction dehydro-NIF diminished hepatocyte donor high basal expression. Discussion: These findings demonstrate that buprenorphine, nifedipine, via vary substrate-specific data provide insight into contribution during pregnancy.