Abstract

Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of > 20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women (n=47) during mid-pregnancy (25-28 weeks gestation) and {greater than or equal to} 3 months postpartum, and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid), and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan / dextromethorphan. At 25-28 weeks gestation, taurine conjugated bile acids comprised 23% of the quantified serum bile acids compared to 7% {greater than or equal to} 3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan / dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy.

Significance Statement Bile acid homeostasis is altered in pregnancy and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of FXR ligands, such as bile acids, may contribute to the high interindividual variability in CYP2D6 expression and activity.