Pharmacokinetics and metabolism of pirarubicin in advanced cancer patients.

We have studied the pharmacokinetics and metabolism of pirarubicin (4'-O-tetrahydropyranyldoxorubicin) in six patients included in an EORTC phase II study. Pirarubicin was injected as an i.v. bolus of 5 min on 3 consecutive days at a dose of 20 mg/m2 per day. Blood samples were collected at regular times after each injection. Urine was collected over 12 h periods for 3 days and then over 24 h periods. Pirarubicin and metabolites were extracted on Sep-pak cartridges, and analyzed by HPLC with fluorometric detection. Unchanged pirarubicin followed three similar plasma concentration curves, which could be fitted by a two-compartment model with successive half-lives of 22.0 min and 12.7 h. Total plasma clearance of the drug was 90 l/h/m2 and total volume of distribution 1380 l/m2. Doxorubicin was the main metabolite in plasma after an injection of pirarubicin; its concentration was lower than that of pirarubicin but progressively increased from day to day and exceeded the level of pirarubicin 8 h after the 3rd injection of the drug until the end of the blood sampling. Pirarubicinol and doxorubicinol were also metabolites of pirarubicin in plasma; pirarubicinol followed similar plasma concentration curves during the 3 days of treatment whereas doxorubicinol progressively increased from day to day. Total urinary excretion represented about 6% of the dose injected. The same metabolites as in plasma were found in urine. Whereas the total amount of pirarubicin and pirarubicinol was the same in urine during the 24 h after each injection, the amounts of doxorubicin and doxorubicinol excreted increased from day to day, so that doxorubicin became progressively the main compound in urine after the end of the treatment. The progressive accumulation of pirarubicin metabolites (doxorubicin and doxorubicinol) after the repetitive injections of pirarubicin are probably due to the protracted half-lives of these compounds as compared to that of pirarubicin.