Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

Abstract

In pregnant women, CYP3A activity increases by 100% during the third trimester (T3). Due to logistical and ethical constraints, little is known about the magnitude of CYP3A induction during the first trimester (T1) and second trimester (T2). Our laboratory has shown that sandwichcultured human hepatocytes (SCHH) and HepaRG cells have the potential to predict the magnitude of in vivo induction of CYP3A activity likely to be observed in T1 and T2. Therefore, we incubated SCHH and HepaRG cells with plasma concentrations of various pregnancyrelated hormones (PRHs)-individually or in combination-observed during T1, T2, or T3 in pregnant women. Then, CYP3A activity was measured by 19-OH-midazolam formation. In all three trimesters, only cortisol (C) consistently and significantly induced CYP3A activity, while other individual hormones (progesterone, estradiol, or growth hormones) failed to induce CYP3A activity. At physiologically relevant 13 plasma concentrations, the magnitude of CYP3A induction by C or the combination of all PRHs did not change significantly with gestational age. The pattern of induction of CYP3A activity in SCHH by the hormones was similar to that in HepaRG cells. Based on these data, we conclude that C remains the major inducer of CYP3A activity earlier in gestation. Moreover, we predict that the magnitude of CYP3A induction during T1 and T2 will be similar to that observed during T3 (∼100% increase versus postpartum). This prediction is consistent with the observation of similar increases in T2 and T3 oral clearance of indinavir (a CYP3A cleared drug) versus postpartum.

Pregnancy‐related pharmacokinetic changes

“…There is a similar magnitude of apparent CYP3A induction during all three trimesters of pregnancy ranging from nearly 40% to over 100%. 1,5 The mechanism of CYP3A induction during pregnancy seems to be primarily through increased cortisol concentrations, 22 however, some have suggested that estradiol and progesterone might also contribute. 23 Midazolam is a selective probe for CYP3A activity as its primary, and, for the most part, minor metabolites are formed via CYP3A.…”

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

“…Alternatively, culture conditions can be modified to induce disease-like characteristics (e.g., phospholipidosis, type II diabetes) or mimic specific physiological conditions (e.g., pregnancy) in SCH for the investigation of altered hepatobiliary disposition of drugs. 25,174,175 …”

“…For example, the activity of CYP3A was assessed in human SCH after incubation with pregnancy-related hormones for 72 hr. 25 …”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…The magnitude of pregnancy‐related induction in drug‐metabolizing enzyme activities can be as high as 300%, as suggested by a study of the kinetics of lamotrigine, a substrate drug of UGT1A4 . The causative mechanisms of hepatic CYP activity changes are believed to be regulated by rising concentrations of various hormones (e.g., estradiol, progesterone, or growth hormones) . The renal excretion of unchanged drugs is increased during pregnancy owing to an increase in the glomerular filtration rate and also possibly to an increase in renal secretion via transporters.…”

“…18 The causative mechanisms of hepatic CYP activity changes are believed to be regulated by rising concentrations of various hormones (e.g., estradiol, progesterone, or growth hormones). 19 The renal excretion of unchanged drugs is increased during pregnancy owing to an increase in the glomerular filtration rate and also possibly to an increase in renal secretion via transporters. Currently, there is evidence relating to the pregnancy effect on renal transporter organic cation transporter (OCT) and intestinal/ renal transporter P-glycoprotein, based on metformin 20 and digoxin data.…”