Pharmacokinetics of a new thienodiazepine platelet activating factor receptor antagonist (E6123) in laboratory animals. Is there a metabolic polymorphism in the rhesus monkey?

Abstract

1. The pharmacokinetics of E6123, a platelet activating factor receptor antagonist, were studied after i.v. and oral administration to rat, guinea-pig, dog and rhesus monkey. Plasma concentrations of E6123 were determined by h.p.l.c. with UV detection.

2. After i.v. dosing (1 mg/kg), the plasma concentration-time curves fitted a two-compartment model. The half-lives for the terminal phases (t_1/2) in rat, dog, and guinea-pig showed very little inter-individual variation, but t_1/2 in the monkey (n = 4) varied more than four-fold. The distribution parameters were very similar in rat, dog and monkey (V_c and V_ss approx. 1.2 and 1.51/kg, respectively) but slightly higher values were found in the guineapig, which also showed the lowest plasma protein binding.

3. After oral dosing (1 mg/kg), the maximum plasma concentrations were obtained within 0.3–3.0 h in all species. The half-life for each individual animal was almost the same as that after i.v. dosing. The mean bioavailabilities of E6123 in rat, guinea-pig and dog were about 65, 95 and 81%, respectively, but the values for monkey were again highly variable (range 32-99%).

4. The high variability in the monkey was confirmed by i.v. administration to a further 10 animals. The mean half-lives for the terminal phase in extensive metabolizers (EMs) (n = 4) and poor metabolizers (PMs) (n=10) were approx. 1 and 4h, respectively.

5. The rank order for total body clearance of E6123 was: rat>monkey (EMs)>dog>guinea-pig>monkey (PMs).