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 0.19 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.
Lindberg-Freijs
A
A
Department of Pharmacy, Uppsala University, Sweden.
Karlsson
M O
MO
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012984:Software; D014018:Tissue Distribution
D016572:Cyclosporine