APRIKALIM - RADIOIMMUNOASSAY AND PHARMACOKINETIC STUDIES IN MOUSE, MONKEY, AND DOG

A stereoselective and specific radioimmunoassay (RIA) was developed for aprikalim (RP 52891), a novel potassium channel opener. Antibodies were produced in rabbits immunized with the pure levorotatory enantiomer (1R,2R) of the hapten derivative bearing an acid function at the end of the lateral chain and conjugated to bovine serum albumin. In displacement studies with the enantiomerically pure radioligand (radioiodinated tyrosine methyl ester conjugate of the hapten derivative), the opposite enantiomer showed only 0.1 % crossreaction. Negligible binding occurred when analogues or metabolites of aprikalim were tested for cross-reactivity. The detection limit was 0.25 ng/mL (9.31 X 10(-10) M) in a 20-mu L plasma sample. The assay was used successfully to determine aprikalim pharmacokinetics in mice, monkeys, and dogs. Beagle dogs were given a 10 mu g/kg intravenous (iv) bolus dose or 10 mu g/kg iv bolus followed by 0.1 mu g/kg/min infused over 30 min (nonhypotensive doses which reduce myocardial infarct size significantly). The plasma concentrations declined monoexponentially with a mean overall elimination half-life of 1.53 h and a mean plasma clearance of 52 mL/min (5.1 mL/min/kg). A slow-release oral formulation produced a significant delay in the rate of absorption, a 4-fold decrease in the peak plasma level, and a 2-fold decrease in apparent oral bioavailability relative to that observed for an oral solution. A comparison of aprikalim pharmacokinetic parameters in mouse, monkey, and dog revealed great similarity in disposition characteristics in these species.