Human pharmacokinetics of N-L-leucyl-doxorubicin, a new anthracycline derivative, and its correlation with clinical toxicities.

A pharmacokinetic study of N-l-leucyl-doxorubicin, a new derivative of doxorubicin, has been undertaken during a phase I trial in 19 patients with advanced cancer after intravenous bolus administration at doses ranging from 30 to 240 mg/m2. The pharmacokinetics of N-l-leucyl-doxorubicin was linear with a total body clearance of 41.3 ± 25.7 L/hr/m2. N-l-Leucyl-doxorubicin was extensively metabolized into doxorubicin, which appeared in plasma immediately after N-L-leucyl-doxorubicin infusion. The mean molar doxorubicin/N-l-leucyl-doxorubicin area under the curve (AUC) ratio was 0.49 ± 0.22 and was independent of the administered dose. A relationship has been established between the doxorubicin AUC (r = 0.74; p < 0.001) and the surviving factor in white blood cell counts. Other toxic side efects (thrombocytopenia or stomatitis) did not correlate with any pharmacokinetic parameter. These findings suggest that the degree of metabolization of N-l-leucyl-doxorubicin into doxorubicin may be responsible for the toxicity, that is, N-l-leucyl-doxorubicin may simply represent a pro-drug for doxorubicin. Clinical Pharmacology and Therapeutics (1992) 51, 249–259; doi:10.1038/clpt.1992.19