Pharmacokinetics of a new antitumor 3-arylisoquinoline derivative, CWJ-a-5

Abstract

1-(4-Methylpiperazinyl)-3-phenylisoquinoline hydrochloride (CWJ-a-5) is a newly developed from benzo[c]phenanthridine alkaloids and derivative and has exhibited potent antitumor activities, in vitro and in vivo. The pharmacokinetics of this novel antitumor 3-arylisoquinoline derivative was studied after intravenous (iv), oral (po) and hepatoportal (pv) administration in rats. A simple high performance liquid chromatographic method was developed to determine the concentrations of CWJ-a-5 in plasma, bile and urine. Plasma concentration profiles of CWJ-a-5 were best fitted by the two-compartment model after iv administration and showed a linear pharmacokinetic behavior up to 20 mg/kg doses. The half-life of CWJ-a-5 in the post-distributive phase ( t 1/2β), total-body plasma clearance ( CL t), and volume of distribution at steady-state ( Vd ss) were 86.9 min, 5.72 l/h per kilogram and 9.79 l/kg, respectively, after iv administration of 10 mg/kg. Biliary and urinary excretion of CWJ-a-5 was <1% after iv injection of 10 mg/kg. The bioavailability of CWJ-a-5 after po and pv administration (50 and 10 mg/kg, respectively) was 52.9 and 72.2%, respectively. Gastrointestinal bioavailability was calculated to be 73.3%. The apparent partition coefficient (log P) of CWJ-a-5 between n-octanol and water was 2.64. Plasma protein binding of CWJ-a-5 measured by the ultrafiltration method was >95%.