Cyclosporin A in Fat Emulsion Carriers: Experimental Studies on Pharmacokinetics and Tissue Distribution

Abstract

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.

Analysis of Volatile Compounds and Triglycerides of Seed Oils Extracted from Different Poppy Varieties (Papaver somniferum L.)

“…Today poppy seed oil is especially used as adjuvant for pharmaceutical and medicinal diagnostics besides its application as a high-quality and delicious edible oil (10). Poppy seed oil is used, for example, as a carrier for cancerostatics in the treatment of hepatocellular carcinoma (11) and as a carrier for cyclosporin A (12). Iodized poppy seed oil can be used for correcting iodine deficiency (13) and as a diagnostic adjuvant for sonography, hysterosalpingography, and angiography (14).…”

Lipid Carriers: A Versatile Delivery Vehicle for Proteins and Peptides

“…52 Site speciˆc delivery can be designed by attaching ligands speciˆc for cellular receptors to the surface of the emulsion globules. 54,55) Provide possibilities for preparing better tolerated intravenous formulations of poorly soluble drugs.…”

Injectable Lipid Emulsions—Advancements, Opportunities and Challenges

“…If the drug release rate from the emulsions is very slow, drug release occurs via natural fat metabolism by the liver parenchymal cells or the drug loaded droplets are cleared by MPS. Molecules with relatively lower log P values, e.g., cyclosporine (log P 2.92) and KW-3902 (log P 4.7), and which are rapidly released from the emulsion system, will in most cases show tissue distribution profile similar to that observed with a solution formulation (107)(108)(109). However, drugs with lower log P values but demonstrating increased steady-state partitioning into the oil phase, or compounds with high log P values, may demonstrate a different tissue distribution profile depending on the formulation components, metabolic fate, enterohepatic recirculation, and other factors (114,117).…”

“…These studies demonstrate that emulsions may or may not have a significant impact on the distribution and elimination of drugs. Several molecules formulated as emulsions have exhibited pharmacokinetic parameters similar to that of a solution dosage form (107)(108)(109)(110)(111)(112). One of the main reasons for not observing any difference has been attributed to a rapid release of the drug from the emulsion.…”

“…• No significant difference in PK parameters and tissue distribution between solution and emulsion (108,157) Solution: Sandimmune® Emulsion: SO:EYPC (~200 nm) Docetaxel (log combination with other emulsions, has been demonstrated to alter systemic clearance and peripheral tissue uptake (127,128).…”