title: 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 sandwich-cultured 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 pregnancy-related hormones (PRHs)-individually or in combination-observed during T1, T2, or T3 in pregnant women. Then, CYP3A activity was measured by 1'-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 1× 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.
authors: Department of Pharmaceutics, University of Washington, Seattle, Washington (Z.Z., M.F., B.P., J.D.U.); and Life Technologies, Carlsbad, California (S.G.).
authors: Zufei
authors: Z
authors: Zhang
authors: Department of Pharmaceutics, University of Washington, Seattle, Washington (Z.Z., M.F., B.P., J.D.U.); and Life Technologies, Carlsbad, California (S.G.).
authors: Muhammad
authors: M
authors: Farooq
authors: Department of Pharmaceutics, University of Washington, Seattle, Washington (Z.Z., M.F., B.P., J.D.U.); and Life Technologies, Carlsbad, California (S.G.).
authors: Bhagwat
authors: B
authors: Prasad
authors: Department of Pharmaceutics, University of Washington, Seattle, Washington (Z.Z., M.F., B.P., J.D.U.); and Life Technologies, Carlsbad, California (S.G.).
authors: Sue
authors: S
authors: Grepper
authors: Department of Pharmaceutics, University of Washington, Seattle, Washington (Z.Z., M.F., B.P., J.D.U.); and Life Technologies, Carlsbad, California (S.G.) jash@u.washington.edu.
authors: Jashvant D
authors: JD
authors: Unadkat
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism*; D008954:Models, Biological; D009994:Osmolar Concentration; D011247:Pregnancy / Q000097:blood / Q000502:physiology*; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D011374:Progesterone / Q000097:blood / Q000378:metabolism
chemical_list: D019382:Human Growth Hormone; D011374:Progesterone; D004958:Estradiol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone