Pharmacokinetics of 480156-S in Healthy Volunteers

Abstract

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 (CL_r), glucuronidation clearance (CL_g) and oxidative metabolismclearance (CL_m) 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.