Cyclosporin A in fat emulsion carriers: experimental studies on pharmacokinetics and tissue distribution.
In the commercially available intravenous formulation of Cyclosporin A (Sandimmun), polyoxyethylated castor oil (Cremophor EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.
Tibell
A
A
Department of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
Lindholm
A
A
Säwe
J
J
Chen
G
G
Norrlind
B
B
D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005217:Fat Emulsions, Intravenous / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013024:Soybean Oil / Q000493:pharmacokinetics*; D013552:Swine; D014018:Tissue Distribution
D004337:Drug Carriers; D005217:Fat Emulsions, Intravenous; D013024:Soybean Oil; D016572:Cyclosporine