Dose dependent absorption and linear disposition of cyclosporin A in rat

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 0·191 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.