Dose dependent absorption and linear disposition of cyclosporin A in rat

✍ Scribed by A. Lindberg-Freijs; M. O. Karlsson

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: English
• Weight: 634 KB
• Volume: 15
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510150107

✦ Synopsis

The pharmacokinetics of cyclosporin A (CyA) were investigated in the rat following intravenous doses of 1.7, 3 . 3 , and 6-4mg kg-' and oral doses of 3.1, 6.8, and 12.9 mg kg-I . The blood concentration-time profile after intravenous administration was adequately described by a twocompartment model when all data were simultaneously analysed using NONMEM. The disposition pharmacokinetics were linear over the dose range studied; the average total blood clearance was 0.19 1 g-' kg-I. The absorption process could not be adequately described by either a first-or a zero-order input.

Therefore, a flexible, staircase input model was used and found to be superior to the standard models. The shape of this model was biphasic, with a higher initial input rate than expected from first-order absorption. The duration of this first phase increased with dose. The extent of absorption was also dose dependent. Bioavailability was higher at higher doses; the values were 45%, 67% and 76% for the three ascending dose levels. These results strongly indicate a saturable first-pass effect. Since the extraction of CyA in the liver is only 6%, the marked increase in bioavailability of CyA is most likely to be the result of saturated gut wall metabolism.