Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h−1 kg−1), distribution volume (4·4 ± 2·0 L kg−1), mean residence time (9·6 ± 4·1 h) and half‐life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg−1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg−1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.

[1]  G. Lopez-Berestein,et al.  Pharmacokinetics of cyclosporine in bone marrow transplantation: longitudinal characterization of drug in lipoprotein fractions. , 1992, Journal of pharmaceutical sciences.

[2]  M. Rowland,et al.  Absorption kinetics of cyclosporin in the rat , 1992, The Journal of pharmacy and pharmacology.

[3]  Y. Ruckebusch,et al.  Physiology of Small and Large Animals , 1990 .

[4]  P. Ravenscroft,et al.  A Modified Assay for Cyclosporin in Blood Using Solid‐Phase Extraction with High‐Performance Liquid Chromatography , 1988, Therapeutic drug monitoring.

[5]  M. Rowland,et al.  Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients. , 1987, British journal of clinical pharmacology.

[6]  L. Demers,et al.  Critical issues in cyclosporine monitoring: report of the Task Force on Cyclosporine Monitoring. , 1987, Clinical Chemistry.

[7]  D. Cutler.  Definition of mean residence times in pharmacokinetics. , 1987, Biopharmaceutics & drug disposition.

[8]  R. Sawchuk,et al.  Absorption of cyclosporine from rabbit small intestine in situ. , 1986, Journal of pharmaceutical sciences.

[9]  R. Venkataramanan,et al.  Clinical Pharmacokinetics of Cyclosporin , 1986, Clinical Pharmacokinetics.

[10]  T. Starzl,et al.  CYCLOSPORINE METABOLISM AND PHARMACOKINETICS FOLLOWING INTRAVENOUS AND ORAL ADMINISTRATION IN THE DOG1 , 1986, Transplantation.

[11]  R. Venkataramanan,et al.  Stability and availability of cyclosporine in 5% dextrose injection or 0.9% sodium chloride injection. , 1986, American journal of hospital pharmacy.

[12]  D. Holt,et al.  The United Kingdom Cyclosporin Quality Assessment Scheme. , 1986, Therapeutic drug monitoring.

[13]  Pippenger Ce.  Cyclosporine quality control program is a reality. , 1985 .

[14]  C. Pippenger.  Cyclosporine quality control program is a reality. , 1985, Therapeutic Drug Monitoring.

[15]  M. Lemaire,et al.  Apparent dose-dependent oral absorption of cyclosporin A in rats. , 1984, Biopharmaceutics & drug disposition.

[16]  N. Rawlings.  THE SHEEP AS AN EXPERIMENTAL ANIMAL. , 1984 .

[17]  P. Sonneveld,et al.  Evidence for a possible dose-dependent pharmacokinetics of Cyclosporin-A in the rat. , 1984, Research communications in chemical pathology and pharmacology.

[18]  D. Perrier,et al.  Noncompartmental determination of the steady-state volume of distribution for any mode of administration. , 1982, Journal of pharmaceutical sciences.

[19]  A. Downes,et al.  A metabolism cage for sheep , 1963 .