Unbound Intrinsic Formation Clearance of 6β‐Hydroxycortisol Is a Useful Biomarker of CYP3A4 Activity during Pregnancy

Pregnancy results in multiple physiological changes that impact drug disposition. For example, hepatic CYP3A activity and renal transporter‐mediated clearance increase in late pregnancy, but the time course of these changes across pregnancy is not known. Endogenous biomarkers offer a minimally invasive approach to characterize pharmacokinetic changes during pregnancy and postpartum. The goal of this study was to determine whether 6β‐OH‐cortisol formation clearance (CL f,OHCOL ) can be used as a biomarker of hepatic CYP3A activity during pregnancy. Thus, we measured cortisol, cortisone, and 6β‐OH‐cortisol in plasma and urine from 47 women during late pregnancy and postpartum and calculated the CL f,OHCOL , unbound fraction (f u ), unbound intrinsic CL f (CL f,u,int,OHCOL ), and renal clearance (CL r ). CL f,OHCOL increased 1.3‐fold in late pregnancy while cortisol f u decreased significantly. CL f,u,int,OHCOL increased 1.8‐fold, corresponding to a 2.1‐fold increase in hepatic CYP3A activity. The increase in CL f,u,int,OHCOL was observed in CYP3A5 expressors and in CYP3A5 nonexpressors. In late pregnancy, the increase in CL r,cortisol and CL r,OHCOL exceeded the calculated increase in filtration clearance, suggesting increased transporter‐mediated secretion. The decreased f u of cortisol during pregnancy was captured by a model incorporating increased expression of corticosteroid binding globulin (CBG) and increased binding affinity of cortisol to CBG. These data suggest that CL f,u,int,OHCOL is a robust biomarker of CYP3A activity during pregnancy and could be used in future studies to characterize the time course of changes in CYP3A activity across gestation and postpartum. Further, CL r,cortisol and CL r,OHCOL may be biomarkers of kidney OCT and MATE activity and could be used to evaluate kidney transporter activity during pregnancy.