Mitomycin C pharmacokinetics in patients with recurrent or metastatic colorectal carcinoma

Abstract

The pharmacokinetics of mitomycin C as a single agent have been determined in 25 treatment courses given to 18 patients with recurrent or metastatic colorectal carcinoma using a high performance liquid chromatography (HPLC) assay to analyze plasma and urine samples. The plasma pharmacokinetics conformed to a two-compartment linear model in 21 of 25 courses monitored with a mean t1/2 lambda 1 of 9.8 +/- 1.2 (SEM) min and mean t1/2 lambda z of 64.1 +/- 8.9 (SEM) min. The large variation observed in t1/2 lambda z was not related to dose or treatment, but an interaction of these two factors approached significance (p = 0.057). Renal excretion in the 12 courses in which it was determined averaged only 2.3% of the total administered dose during the first 4 h monitored and no mitomycin C metabolites were detected in plasma or urine by the HPLC technique used. The most common toxicity, thrombocytopenia, did not correlate with t1/2 lambda z or the area under the curve. This may be due to a failure to monitor active metabolites of mitomycin C; other factors besides plasma drug concentrations that mediate toxicity towards marrow elements; or the small number of courses associated with thrombocytopenia (less than 100,000/mm3). Our study indicates that an interaction of drug dose and treatment course may be associated with increasing t1/2 lambda z; the renal clearance contributes a small component of mitomycin C elimination; metabolites of mitomycin C cannot be detected by the present HPLC technique; and routine monitoring of mitomycin C using present methods cannot be recommended for clinical use to predict toxicity.