Regulation of phase I, II, and III pathways by pregnancy related hormones

Clinical studies have indicated that pregnancy alters the pharmacokinetics profiles of several medications. Results from previous studies have suggested that physiological changes that occur in pregnancy, including increased plasma concentrations of female hormones may play an important role in the observed changes in drug metabolism. Despite this general awareness, the mechanisms underlying the regulation of major drug metabolizing enzymes such as cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) during pregnancy remain unknown. The aim of this dissertation was to characterize the impact of pregnancy related hormones on hepatic CYPs, UGTs and transporters.;The effect of female hormones on the expression and activity of selected CYP, UGT, and transporters was measured in four independent studies in primary cultures of human hepatocytes. A mixture of female hormones at projected hepatic concentrations in the third trimester of pregnancy significantly increased mRNA expression, activity, and protein expression of CYP3A4 but limited impact on other CYPs. Female hormones however, differentially altered the expression and activity of various UGT enzymes. Progesterone and estradiol increased the activities of UGT1A1 and UGT1A4, respectively. Conversely, human chorionic gonadotropin decreased the activity of UGT1A4. A significant increase in the expression of UGT1A6 and UGT1A9 was observed by progesterone compared to the control. Human growth hormone enhanced the mRNA expression of UGT2B7. Expression of UGT1A1, UGT1A3 and AhR were significantly increased by estradiol. Progesterone significantly increased the expression of BCRP. Estradiol also enhanced the expression of NHERF1. Together, these findings provide support for the role of female hormones in the altered specific drug metabolism and transport during pregnancy.;Using physiological based pharmacokinetics (PBPK) modeling, we predicted that pregnancy will increase the clearance of buprenorphine (a drug that is simultaneously metabolized by CYP and UGT). This was supported by preliminary clinical observations. However, female hormones did not have any significant impact on the metabolism of buprenorphine in primary cultures of human hepatocytes, implicating additional factors to be responsible for pregnancy-mediated changes in pharmacokinetics of buprenorphine.;In conclusion, our findings indicate that pregnancy related hormones contribute to some of the observed changes in drug metabolism and transport during pregnancy.