RT Journal Article
SR Electronic
T1 Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 296
OP 304
DO 10.1124/dmd.112.044891
VO 41
IS 2
A1 Shringi Sharma
A1 Ewa C. S. Ellis
A1 Roberto Gramignoli
A1 Kenneth Dorko
A1 Veysel Tahan
A1 Marc Hansel
A1 Donald R. Mattison
A1 Steve N. Caritis
A1 Ronald N. Hines
A1 Raman Venkataramanan
A1 Stephen C. Strom
YR 2013
UL http://dmd.aspetjournals.org/content/41/2/296.abstract
AB Little information is available in the literature regarding the expression and activity of transporters in fetal human liver or cultured cells. A synthetic progesterone structural analog, 17α-hydroxyprogesterone caproate (17-OHPC), is used in the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion). 17-OHPC has been reported to traverse the placental barrier and gain access to fetal circulation. In this study, the role of transporters in the disposition of 17-OHPC in fetal and adult human hepatocytes was examined. Progesterone metabolites have been reported to induce trans-inhibition of bile acid transporter, ABCB11. Thus, we investigated the effect of 17-OHPC or its metabolites on [3H]taurocholic acid transport in sandwich-cultured human fetal and adult hepatocytes. 17-OHPC was taken up rapidly into the cells and transported out partially by an active efflux process that was significantly inhibited by cold temperature, cyclosporine, verapamil, and rifampin. The active efflux mechanism was observed in both adult and fetal hepatocyte cultures. 17-OHPC produced a concentration-dependent inhibition of taurocholate efflux into canaliculi in sandwich-cultured adult and fetal human hepatocytes. However, given the high concentrations required to cause inhibition of these transport processes, no adverse effects would be anticipated from therapeutic levels of 17-OHPC. We also evaluated the expression of various hepatic transporters (ABCB1, ABCB4, SLCO1B1, SLCO1B3, SLCO2B1, ABCB11, SLC10A1, ABCC2, ABCC3, ABCC4, and ABCG2) in fetal and adult hepatocytes. With the exception of ABCB4, all transporters examined were expressed, albeit at lower mRNA levels in fetal hepatocytes compared with adults.