Abstract
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 Cmax, a reduction oftmax, 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.
Footnotes
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Send reprint requests to: Dr. Jean-Claude Montet, INSERM, Laboratoire de Physiopathologie Hépatique, 46 Boulevard de la Gaye, 13009, Marseille, France.
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This work was supported in part by grants from the Association Française de Lutte contre la Mucoviscidose (AFLM), Paris, France. This work was presented in part at the American Gastroenterological Association, New Orleans, LA, May 15–18, 1994.
- Abbreviations used are::
- CsA
- cyclosporin A
- UDC
- ursodeoxycholate
- TUDC
- tauroursodeoxycholate
- AUC
- area under the blood drug concentration-time curve
- CV
- coefficient of variation
- Received August 9, 1996.
- Accepted April 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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