Species Variation in Pharmacokinetics and Opsonization of Palmitoyl Rhizoxin (RS-1541) Incorporated in Lipid Emulsions

Abstract

Highly lipophilic antitumor agent, palmitoyl rhizoxin (RS-1541), was incorporated into stable lipid emulsions about 100-1000nm in mean diameter consisting of triglyceride ODO and surfactant HCO-60. The pharmacokinetics of RS-1541 were studied after i.v. injection in mice, rats, rabbits, and dogs. Dog showed characteristic pharmacokinetics of RS-1541, compared with other species. RS-1541 was much more rapidly eliminated from plasma with emulsion particles in dogs than in mice, rats, and rabbits. Most amounts of injected RS-1541 were recovered in the liver six hours after administration to dogs, while less than 20% recoveries were observed for mice and rats. To clarify this species variation, opsonization of emulsion particles were evaluated. When emulsions (about 200nm in size) were opsonized by dog plasma, and intravenously injected to rats, total clearance and liver uptake of RS-1541 were increased to 1.8 fold and 2.7 fold of control values, respectively. In contrasts, emulsions opsonized by mouse, rabbit and human plasma did not show such drastic changes in pharmacokinetics of RS-1541 in rats. Furthermore, total clearance of RS-1541 for emulsions opsonized by dog plasma was increased to 1.9 fold of controls after injection to rabbits. These results indicate that opsonizing activities of dog plasma for RS-1541 emulsions are high, compared with other species. This species variation in opsonizing process probably caused the species variation in the pharmacokinetics of RS-1541 incorporated in lipid emulsions.

Key Words:

• Emulsions
• Opsonization
• Pharmacokinetics
• RS-1541 (Palmitoyl Rhizoxin)
• Species Variation