Dose dependent absorption and linear disposition of cyclosporin A in rat

Abstract

The pharmacokinetics of cyclosporin A (CyA) were investigated in the rat following intravenous doses of 1.7, 3.3, and 6.4 mg kg-1 and oral doses of 3.1, 6.8, and 12.9 mg kg-1. The blood concentration-time profile after intravenous administration was adequately described by a two-compartment 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 l g-1 kg-1. 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.