title: Effect of probucol on the oral bioavailability of cyclosporine A.
abstract: We have previously reported the reduction in oral bioavailability of cyclosporine A (CsA) by probucol, a lipid-lowering drug. To evaluate the mechanism, we examined the effect of probucol on the transport of CsA across Caco-2 cell monolayers, on the influence of CsA pharmacokinetics in rats, and on the change of ultraviolet-absorption spectrum of the drug. Pretreatment with probucol (50 microM) inhibited (P < 0.001) both the apical-to-basal (-73.1%) and basal-to-apical (-77.8%) fluxes of [3H]-CsA. In rats, probucol orally given 6 h after, but not simultaneous with CsA did not decrease peak CsA concentration or area under the blood CsA concentration-time curve following a single oral dosing of CsA after the pretreatment with probucol for 7 days. These data indicate that P-glycoprotein-mediated active transport from intracellular to apical is not involved in the mechanism of probucol-CsA interaction, and absorption of CsA decreases in the presence of probucol in the gastrointestinal tract. In difference spectral analysis, probucol reduced the absorption peak of CsA in a concentration-dependent manner, indicating that probucol could form a complex with CsA. These results suggest that probucol interferes with CsA absorption probably by physicochemical mechanism such as complex formation, but not the enhancement of P-glycoprotein function.
authors.affiliation: Department of Pharmacology, Jichi Medical School, 3311-1 Minamikawachi, Tochigi 329-0498, Japan. ksugi@jichi.ac.jp
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sudoh
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsuruoka
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Maezono
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D011341:Probucol / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000924:Anticholesteremic Agents; D016572:Cyclosporine; D011341:Probucol