THE PHARMACOKINETICS AND CARDIOVASCULAR PHARMACODYNAMICS OF HP-749 (BESIPIRDINE HCL) AND METABOLITE P86-7480 IN THE CONSCIOUS MONKEY

HP 749 was absorbed slowly in the conscious monkey after single oral d oses (10, 20, and 40 mg/ kg), with gradual metabolism to the N-desprop yl metabolite, P86-7480. The t(max) was 2 to 4 hours after dosing, wit h nonlinear increases in C-max and the AUC(0-4h) for HP 749. The calcu lated elimination half life (t(1/2)) after oral administration was 7.4 +/- 2.1 hours; however, absorption appeared to influence the terminal phase because the t(1/2) after intravenous administration of 10 mg/kg was 1.5 hours. Plasma concentration of HP 749 2 minutes after intrave nous bolus was 26.08 mu g/mL. The HP 749 was rapidly distributed (t(1/ 2 alpha) = 0.064 +/- 0.033 hours) after intravenous administration, an d displayed a V-Z of 2.6 +/- 0.85 L/kg. The CL of HP 749 was 20.8 +/- 6.9 ml/min/kg, whereas renal clearance (CL(R)) of unchanged drug was o nly 0.13 +/- 0.04 ml/min/kg. Thus, only about 1% of the administered d ose was excreted unchanged by the kidney. The P86-7480 also was rapidl y distributed and eliminated after an intravenous bolus, but was less extensively distributed than HP 749. HP 749 administered either as on intravenous bolus or orally caused a significant presser effect soon a fter dosing. A significant tachycardia resulted from intravenous admin istration, but not after oral administration of the drug. An intraveno us bolus of P86-7480 (0.1 mg/kg) resulted in an immediate increase in MAP and decreased heart rate. The duration of these cardiovascular eve nts was significantly shorter after intravenous administration of P86- 7480 than with intravenous or oral administration of the parent drug. These results support findings of previous studies in rats and dogs, d emonstrating that high doses of HP 749 and its metabolite P86-7480 exe rt significant cardiovascular effects.