Pharmacokinetics of idarubicin in the isolated perfused rat lung: effect of cinchonine and rutin

This study was designed to examine the effect of rutin and cinchonine on the uptake and metabolism of idarubicin (IDA) in the isolated perfused rat lung. IDA (2 mg) was infused for 2 min into the truncus pulmonalis in thepresence of P-glycoprotein (P-gp) modulators cinchonine (1 μM) or rutin (6 μM). (Rutin is also known as an aldo-keto reductase inhibitor.) Venous outflow samples were collected up to 60 min, and the concentration of IDA and its primary metabolite idarubicinol (IDOL) were measured by high-performance liquid chromatography) with fluorescence detection. Thereafter, the tissue concentrations of IDA and IDOL were determined in the lung (n = 5 in each group). The estimated mean transit times for IDA in the treatment groups (MTT c i n c h o n i n e = 21.8′3.5 min; MTT r u t i n = 20.1 ′ 5.0 min) were significantly higher than in the control group (11.6 ′ 2.1 min). Both cinchonine and rutin significantly enhanced the lung tissue concentrations of IDA (1.7- and 2.4-fold), as well as of IDOL (2.1- and 2.4-fold). Cinchonine and rutin also increased the outflow recovery of IDOL 2.6- and 2.7-fold, respectively. The results suggest that uptake kinetics of IDA into the rat lung is partly controlled by a P-gp efflux pump and its inhibition enhances the accumulation of IDA.