Phase I clinical studies of S-1108: safety and pharmacokinetics in a multiple-administration study with special emphasis on the influence on carnitine body stores.

S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 +/- 0.17 h at the first dose to 0.87 +/- 0.18 h at the last dose and from 7.30 +/- 1.10 to 5.20 +/- 0.85 micrograms.h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conjugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 +/- 3.6%, resulting in an increase of daily carnitine urinary excretion two- to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70% of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID.