Pharmacokinetics and toxicity of mitomycin C in rodents, given alone, in combination, or after induction of microsomal drug matabolism

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Abstract
The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD50 value in rats. Most of the drug was metabolized, and only 1%–2% and 10%–15% of the dose was eliminated unchanged by biliary and urinary excretion, respectively. The AUC of MMC at the LD50 is slightly less than that reported for the human MTD. Inoculation of MMC together with 5-fluorouracil and doxorubicin did not change the terminal half-life of MMC but decreased the total body clearance and the volume of distribution. The lack of significant influence of phenobarbital and 3-methylcholanthrene pretreatment on the terminal elimination half-life suggests that microsomal drug-metabolizing enzymes inducible by these compounds do not play a decisive role in the in vivo biotransformation of MMC.