CS-758 (R-120758), a Novel Triazole Antifungal Agent: Pharmacokinetics and Metabolism after Intravenous Administration of a Solution in Hydroxypropyl-àŸ-cyclodextrin (HP-àŸ-CD) to Laboratory Animals

T. SHIBAYAMA1, K. KAWAI1, E. TSUKADA1, Y. MATSUSHITA1, K. OGAWA1, T. KURASAWA1, T. HIROTA1, S. KUWAHARA2

Author address: 

1Res. Labs., Sankyo Co., Ltd., Tokyo, Japan, 2Toho Univ. Sch. of Med., Tokyo, Japan.

Abstract: 

Background: CS-758 (CS) is a new triazole antifungal agent, which is under development as an oral drug (ICAAC 40th). To develop parenteral preparations of CS, the pharmacokinetics and metabolism in animals were investigated after intravenous administration of a HP-b-CD solution of CS. Methods: CS was dissolved in 13.3% HP-b-CD solution and administered intravenously to animals at a dose of 2 mg/kg. Results: Plasma concentrations of CS decreased biexponentially with elimination half-lives of 4.7 and 4.6 hr in rats and monkeys, respectively. Extensive tissue distribution of radioactivity was observed after administration of 14C-CS to rats. The order of the levels at 8 hr post-dose was adrenal glands, liver, fat, kidneys, lungs, skin, muscle, plasma, then brain. The lungs and skin levels of radioactivity were more than twice higher than the corresponding plasma level. On the other hand, the level of radioactivity in the brain was around 0.8 times as much as that in the plasma, suggesting that CS and/or its metabolites did not readily penetrate the blood-brain barrier. Together with the parent drug, the corresponding sulfoxides and a few unknown metabolites were detected in rat plasma. However, the unchanged form was hardly observed in the urine or feces. About 80% of the administered radioactivity was recovered in the feces through biliary excretion after administration of 14C-CS to rats. Conclusion: CS was demonstrated to have a desirable pharmacokinetic profile with good tissue distribution when intravenously administered as a HP-b-CD solution. This profile of CS is comparable with that after oral administration, suggesting that CS can be administered both orally and intravenously.
2001

abstract No: 

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Full conference title: 

ICAAC 41st
    • ICAAC 41st