title: Effect of oral contraceptives on the transport of chlorpromazine across the CACO-2 intestinal epithelial cell line.
abstract: In previous chlorpromazine pharmacokinetic studies a dramatic elevation in blood plasma levels of this drug was observed when taken in combination with oral contraceptives. Different mechanisms have been postulated to explain this observation. The aim of the study was to investigate whether oral contraceptives such as ethinyloestradiol and progesterone enhance the absorption of chlorpromazine by means of inhibiting P-glycoprotein (P-gp) and if this effect is mainly due to ethinyloestradiol or progesterone or their combination. The Caco-2 cell line was used as an in vitro model to study the effects of these compounds on the transport of chlorpromazine. Both apical to basolateral (AP-BL) and basolateral to apical (BL-AP) transport studies were done on chlorpromazine in combination with different compounds. Ethinyloestradiol enhanced the AP-BL cumulative transport of chlorpromazine by 11.5% compared to the control group, which was also statistically significantly higher than the effect caused by progesterone (0.8%). A combination of these two steroidal hormones enhanced the cumulative transport of chlorpromazine by only 2.0% compared to the control group. This indicates the possible existence of separate drug-binding sites for these two hormones and chlorpromazine on P-gp. The drug-binding site (or receptor) for progesterone probably interacts allosterically with the binding site for ethinyloestradiol and thereby decreasing its transport enhancing effects on chlorpromazine.
authors.affiliation: School of Pharmacy, Technikon Pretoria, Pretoria, South Africa.
authors.forename: Deon
authors.initials: D
authors.lastname: Brown
authors.forename: Theunis C
authors.initials: TC
authors.lastname: Goosen
authors.forename: Mano
authors.initials: M
authors.lastname: Chetty
authors.forename: Josias H
authors.initials: JH
authors.lastname: Hamman
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D002746:Chlorpromazine / Q000493:pharmacokinetics*; D003276:Contraceptives, Oral / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism
chemical_list: D003276:Contraceptives, Oral; D002746:Chlorpromazine