Development of Radioimmunoassay for the Novel Platelet Activating Factor Receptor Antagonist, E6123, and Its Application to Pharmacokinetics in Laboratory Animals

• Published in: Biological & pharmaceutical bulletin Vol. 17; no. 2; pp. 334 - 339
• Main Authors: KUSANO, Kazutomi, TADANO, Kyoichi, TANAKA, Shigeru, KAGEI, Yoshiko, UEDA, Masataka, MIYAZAWA, Shuhei, ABE, Yoshihisa, IDA, Satoshi, YUZURIHA, Teruaki
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1994; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Azepines - blood; Azepines - immunology; Azepines - pharmacokinetics; Biological and medical sciences; Biological Availability; Cardiovascular system; Chromatography, High Pressure Liquid; Cross Reactions; Dogs; E6123; Guinea Pigs; Haptens; Immune Sera; laboratory animal; Macaca mulatta; Male; Medical sciences; pharmacokinetics; Pharmacology. Drug treatments; Platelet Activating Factor - antagonists & inhibitors; Rabbits; Radioimmunoassay; Sensitivity and Specificity; Serum Albumin, Bovine; Spectrophotometry, Ultraviolet; Triazoles - blood; Triazoles - immunology; Triazoles - pharmacokinetics; Vasodilator agents. Cerebral vasodilators; Fissipedia; Carnivora; Intravenous administration; Low dose; Rodentia; Monkey; Oral administration; Platelet activating factor; Blood; Vertebrata; Mammalia; Guinea pig; Investigation method; Animal; Radioimmunoassay; Primates; Antagonist; Pharmacokinetics; Dog; Quantitative analysis
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.17.334

A direct radioimmunoassay for the determination of E6123, a novel antagonist of platelet activating factor (PAF) receptor, was developed in order to study the pharmacokinetics at low dose. This procedure used [3H] E6123 as the radioligand and an antiserum obtained from rabbits immunized 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 administration of [14C] E6123 to dogs and monkeys was low. The sensitivity limit of this assay was 25 pg/ml of plasma when 0.1ml 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 HPLC-UV method (r=0.972-0.984, slope=1.0314-1.2143). The pharmacokinetics of E6123 was studied at a dose of 30 μg/kg. After intravenous administration, the plasma concentration-time curves in all species fitted a two-compartment model and the terminal half-lives in guinea pigs, dogs and monkeys (both poor and extensive metabolizers) were 4.77, 1.71, 5.34 and 1.07 h, respectively. After oral administration, the maximum plasma concentrations were obtained within 0.83-3.00 h and the half-life for each animal was almost the same as that after intravenous administration. The mean bioavailabilities of E6123 in guinea pigs, dogs and monkeys (poor and extensive metabolizers) were 106.9, 45.7, 59.1 and 22.8%, respectively.