Mitomycin C pharmacokinetics in rats - effect of dose size

Abstract

The pharmacokinetics of mitomycin C was studied following intravenous administration of the drug at three different dose levels to rats. A rapid high-performance liquid Chromatographic assay was developed for the determination of mitomycin C in plasma and urine. Analysis was performed using a reversed-phase octadecyi silane column and precolumn. The mobile phase consisted of 30% v/v) methanol in water (apparent pH of 4.5) containing 1.0 mM octane sulfonic acid-sodium salt delivered at a rate of 1.0 ml · min −1. The eluent was monitored at 360 nm. Under the conditions, mitomycin C and the internal standard had capacity factors of 1.6 and 3.0, respectively. Samples (50 μ1) of plasma or urine were prepared by alkalinizing the sample with 50 μl of 0.1 M ohosphate buffer solution and extracting with four volumes of 1:1 (v/v) chloroform: 2-propanol mixture. The detection limit was 0.01 μg · ml −1. Over the plasma concentration range of 0.01–10.0 μg · ml −1, the within-day coefficient of variation (CV) ranged from 6 to 16%. The between-day CV ranged from 2 to 18%. The assay was used for pharmacokinetic studies in rats. Logarithm of the olsma concentration-time profiles suggest a biphasic behavior with rapid distribution and dose-dependent elimination phases. At dose levels of 2.5 and 5.0 mg · kg −1, the effective half-lives, mean residence times and total plasma clearance did not show any significant dose dependency. However, at 10 mg · kg −1 dose level, significant increase in effective half-lives, mean residence times and a significant decrease in total plasma clearance were observed. Only 2–8% of the administered dose appeared as intact drug in the urine, whereas no fecal excretion of the drug was observed. At different dose levels, the disposition is linear with the half-lives becoming longer after the higher doses. This finding may either be attributed to the inhibition of the NADPH-linked cytochrome reductase system or to the rapid tissue uptake followed by slow release of the drug from tissue storage site.