Pharmacokinetics of 480156-S in healthy volunteers.

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2- [4-(2-Thiazolyloxy) phenyl] propionic acid (156-S) is a new acidic nonsteroidalanti-inflammatory and analgesic agent. Metabolism studies of 156-S in animals andhumans have revealed the metabolic and elimination pathways, but no pharmacokineticstudies in humans have been completed. In this study, the pharmacokinetics of 156-S in healthy volunteers was investigated.Six healthy male volunteers were given 156-S orally at doses of 100, 200, and 400 mgwith at least one week's interval and six other healthy male volunteers participated in amultiple-dose study of 300 mg t. i. d. for 21 days. Plasma and urine concentrations of156-S and its metabolites were determined by HPLC. The pharmacokinetic parameterswere estimated using the one-compartment model. Serum protein binding wasdetermined by equilibrium dialysis. In the single-dose studies, urinary recoveries at each dose were almost 100%independent of the dose, but the AUC increased more than proportional to the doses andthe half-life became longer as the dose increased, suggesting nonlinearity in thepharmacokinetics of 156-S. In the multiple-dose study, half-lives at the 22nd, 43rd and 64th doses were almosttwice that at the 1st dose and AUCs were almost three-fold, although urinary recoveriesat each dosing interval were almost constant at about 90%. Protein binding of 156-S was98% and the binding was not affected by multiple dosing. These results suggest thatsome parts of elimination pathways are inhibited during multiple administration. Amongrenal clearance (CLr), glucuronidation clearance (CLg) and oxidative metabolismclearance (CLm) of 156-S calculated by dividing the urinary excreted amount byplasma concentration, only CLm was reduced significantly during multiple administration.This oxidative metabolism inhibition was shown to be a reversible phenomenonand to recover after a washout period of a few days. However we must investigate theinteraction with other drugs which are eliminated by oxidative metabolism.
一般社団法人日本臨床薬理学会の論文

Pharmacokinetics of 480156-S in healthy volunteers.

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