Pharmacokinetics and disposition of CS-0777, a sphingosine 1-phosphate receptor modulator, in rats and monkeys

1. Disposition and metabolism of CS-0777 (1-{5-[(3R)-3-amino-4-hydroxy-3- methylbutyl]-1-methyl-1H-pyrrol-2-yl}-4-(4-methylphenyl) butan-1-one), a selective sphingosine 1-phosphate receptor-1 modulator under development for autoimmune conditions was investigated following oral and/or i.v. bolus administration to rats and monkeys. 2. After oral administration of [14C]CS-0777, CS-0777 was well absorbed in rats and monkeys with total recoveries of over 90% of the dose, majorly in feces. CS-0777 and phosphorylated pharmacologically active metabolite of CS-0777 (M1) were highly bound to plasma proteins among rats, monkeys and humans (>93%). 3. The structures of 12 metabolites were identified and phosphorylation and two hydroxylation pathways were proposed as primary metabolism. In the blood of rats and monkeys, the major metabolite was M1 and a few phosphorylated metabolites were also detected. Meanwhile, in urine and feces of rats and monkeys, not phosphorylated, but oxidized CS-0777 metabolites and/or those various conjugated metabolites were observed. This suggests that CS-0777 and its oxidized metabolites would be phosphorylated in the body, but their phosphorylated metabolites would revert back to their dephosphorylated form again then be further metabolized and finally eliminated from the body. 4. Pharmacokinetic analysis using a reversible metabolism model revealed that the clearance of phosphorylation was larger than the clearance of dephosphorylation and elimination.