0090-9556/97/2508-0912-0916$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 8

Effects of Tauroursodeoxycholate Solutions on Cyclosporin A Bioavailability in Rats

Nathalie Balandraud-Pieri, Pierre-Edouard Queneau, François-Xavier Caroli-Bosc, Pierre Bertault-Pérès, Anne-Marie Montet, Alain Durand, and Jean-Claude Montet

INSERM, Laboratoire de Physiopathologie Hépatique (N.B.-P., P.-E.Q., F.-X.C.-B., A.-M.M., J.-C.M.) and Laboratoire de Pharmacocinétique et de Toxicocinétique (P.B.-P., A.D.)

Cyclosporin A (CsA) exhibits poor bioavailability after oral administration of Sandimmune, with wide intra- and interindividual variations. Our study sought to determine the effect of the coadministration of CsA standard oily formulation and tauroursodeoxycholate (TUDC) and that of an aqueous micellar solution containing TUDC, monoolein, and CsA in promoting and regulating CsA bioavailability in the rat. Pharmacokinetic parameters of CsA were determined in fasted rats after either an intravenous administration (5 mg/kg) or a single oral CsA dose of 10 mg/kg. Compared with oral Sandimmune, the CsA micellar solution significantly improved the CsA bioavailability by 160% and decreased the interindividual variability in bioavailability expressed as percent coefficient of variation from 32% to 15%. The concentration-time profile was modified with a 3.5-fold increase in C_max, a reduction of t_max, and an increased trough concentration. Bioavailability slightly improved in rats receiving standard oily solution plus concomitant TUDC, although not significantly. Data indicate that the structure of the CsA carriers greatly affect drug bioavailability and that aqueous micellar solutions of CsA-TUDC-monoolein constitute efficient vehicles, thus providing for CsA high absorption with low variability.