CS-758 (R-120758), a Novel Triazole Antifungal Agent: Pharmacokinetics and Metabolism in Monkeys


Author address: 

1Res. Labs., Sankyo Co., Ltd., Tokyo, Japan, 2Huntingdon Life Sciences Ltd., Cambridgeshire, United Kingdom, 3Toho Univ. Sch. of Med., Tokyo, Japan.


Background: CS-758 (CS) is a new triazole antifungal agent, which is under development as an oral drug (ICAAC 40th). Methods: The pharmacokinetics and metabolism of CS were investigated in cynomolgus monkeys. CS was dissolved in 5% DMSO and 20% Tween80 solution for the oral preparation and in 7.5% ethanol and 10% vitamin E-TPGS solution for the intravenous preparation. Results: Plasma concentrations of CS reached the maximum level, 0.85 µg/ml, at around 3 hr after oral administration at a dose of 5 mg/kg. When administered intravenously at a dose of 2 mg/kg, plasma concentrations of CS decreased biexponentially with an elimination half-life of 4.6 hr, and total body clearance and distribution volume at steady state were estimated to be 7.7 ml/min/kg and 2.3 L/kg, respectively. The oral absolute bioavailability was 99.6%, indicating that CS was almost completely absorbed in monkeys. After oral and intravenous administration of 14C-CS, besides the unchanged form of CS, the corresponding sulfoxides, amide and a few unknown metabolites were detected in plasma. A small amount of the unchanged form, the sulfoxides and the amide were also detected in the feces, but hardly observed in the urine. When CS was incubated in vitro with monkey and human liver microsomes, the sulfoxides and the amide were produced. About 60% of the administered radioactivity was recovered in the feces after intravenous administration,suggesting that more than half of the radioactivity in the body was excreted into the bile. Conclusion: CS was demonstrated to have a pharmacokinetic profile with high oral absorption and favorable distribution in monkeys. These pharmacokinetic properties of CS suggest that CS would be desirable in treatment of fungal infections.

abstract No: 


Full conference title: 

ICAAC 41st
    • ICAAC 41st