DEVELOPMENT OF RADIOIMMUNOASSAY FOR THE NOVEL PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONIST, E6123, AND ITS APPLICATION TO PHARMACOKINETICS IN LABORATORY-ANIMALS

A direct radioimmunoassay for the determination of E6123, a novel anta gonist of platelet activating factor (PAF) receptor, was developed in order to study the pharmacokinetics at low dose. This procedure used [ H-3]E6123 as the radioligand and an antiserum obtained from rabbits im munized with the hapten covalently bound to bovine serum albumin. M1B, one of the main metabolites of E6123, exhibited cross-reactivity with antisera. But this metabolite had no effect on measurements of E6123, because the amount of M1B in plasma radioactivity after administratio n of [C-14]E6123 to dogs and monkeys was low. The sensitivity limit of this assay was 25 pg/ml of plasma when 0.1 ml of plasma was used and the assay showed good accuracy and high precision. The validity of the radioimmunoassay was demonstrated by comparative analysis of a number of samples after oral and intravenous administration (1.0 mg/kg) by H PLC-UV method (r = 0.972-0.984, slope = 1.0314-1.2143). The pharmacoki netics of E6123 was studied at a dose of 30 mu g/kg. After intravenous administration, the plasma concentration-time curves in all species f itted a two-compartment model and the terminal half-lives in guinea pi gs, dogs and monkeys (both poor and extensive metabolizers) were 4.77, 1.71, 5.34 and 1.07 h, respectively. After oral administration, the m aximum plasma concentrations were obtained within 0.83-3.00 h and the half-life for each animal was almost the same as that after intravenou s administration. The mean bioavailabilities of E6123 in guinea pigs, dogs and monkeys (poor and extensive metabolizers) were 106.9, 45.7, 5 9.1 and 22.8%, respectively.