Role of the carrier solution in cyclosporine pharmacokinetics in the baboon

Although numerous investigational models have demonstrated the potent immunosuppressive properties of cyclosporine, the effectiveness of any given dosage may vary with the metabolism of the animal, the route of administration, and the carrier solution of the drug. We investigated the pharmacokinetics of intramuscular cyclosporine administration in the baboon using three carriers: polyoxethylated castor oil (Cremophor), a mixture of octanoic and decanoic acids (Miglyol), and olive oil. Cyclosporine prepared in Cremophor, Miglyol, or olive oil was injected intramuscularly into the hindlegs of baboons. Specimens for cyclosporine assay were obtained 2, 4, 6, 12, 18, and 24 hours after single intramuscular injection of 10 mg/kg or 15 mg/kg. In addition, weekly, then monthly, levels were obtained on animals receiving daily intramuscular injections following heterotopic heart xenografts. Attempts at oral administration proved unreliable and were discontinued. Cyclosporine assay was performed on stored serum using the RIA-KIT (Sandoz Pharmaceuticals Corporation, East Hanover, N.J.). Cremophor provides a more bioavailable form of cyclosporine than Miglyol when administered intramuscularly. (Area under curve = 7776 +/- 1437 for Cremophor 15 mg/kg vs 1837 +/- 726 for Miglyol 15 mg/kg; 2579 +/- 694 for Cremophor 10 vs 1123 +/- 393 for Miglyol 10.) Long-term daily intramuscular administration of Cremophor provides a sustained drug serum trough level with wide variability between individual animals (80 to 825 ng/ml). Toxicity was limited to injection site inflammation. There was no biochemical evidence of renal toxicity; however, some animals did demonstrate early histologic changes of cyclosporine effect.(ABSTRACT TRUNCATED AT 250 WORDS)