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

A stereoselective and specific radioimmunoassay (RIA) was developed fo r aprikalim (RP 52891), a novel potassium channel opener. Antibodies w ere produced in rabbits immunized with the pure levorotatory enantiome r (1R,2R) of the hapten derivative bearing an acid function at the end of the lateral chain and conjugated to bovine serum albumin. In displ acement studies with the enantiomerically pure radioligand (radioiodin ated tyrosine methyl ester conjugate of the hapten derivative), the op posite enantiomer showed only 0.1 % crossreaction. Negligible binding occurred when analogues or metabolites of aprikalim were tested for cr oss-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 determi ne 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 b olus followed by 0.1 mu g/kg/min infused over 30 min (nonhypotensive d oses which reduce myocardial infarct size significantly). The plasma c oncentrations declined monoexponentially with a mean overall eliminati on half-life of 1.53 h and a mean plasma clearance of 52 mL/min (5.1 m L/min/kg). A slow-release oral formulation produced a significant dela y in the rate of absorption, a 4-fold decrease in the peak plasma leve l, and a 2-fold decrease in apparent oral bioavailability relative to that observed for an oral solution. A comparison of aprikalim pharmaco kinetic parameters in mouse, monkey, and dog revealed great similarity in disposition characteristics in these species.