Pharmacokinetics of the 9-amino and 10,11-methylenedioxy derivatives of camptothecin in mice

Abstract

Although 20(S)-camptothecin (CA) exhibited potent cytotoxicity against a broad spectrum of tumor models, clinical trials with the sodium salt of its opened lactone ring form were discontinued due to highly variable and severe toxicity. Recently, the 9-amino (AC) and 10,11-methylenedioxy (MC) derivatives of CA were selected for preclinical evaluation by the National Cancer Institute. In the present investigation, the pharmacokinetic behavior of CA, its sodium salt CA, AC, and MC in mice was characterized using specific liquid chromatographic assays which permitted determination of the intact lactone and opened ring carboxylate forms of these compounds. CA disposition was triexponential with a prolonged terminal phase that had a 24.6-h half-life (t1/2,z) that comprised only 14.6% of the area under the concentration-time profile. The relative magnitudes of the total body apparent volume of distribution (Vz) and terminal phase rate constant suggest that the high observed total plasma clearance (CL, 104 ml/min/kg) may be associated with extensive accumulation in peripheral tissue regions from which the drug is slowly released. In comparison, the terminal disposition phase of MC accounted for 49.7% of the area under the curve profile. It also had a shorter t1/2,z (15.2 h) and appreciably greater CL (526 ml/min/kg) and Vz (694 liters/kg). This suggested that the degree of binding to tissues relative to plasma proteins was enhanced by the methylenedioxy moiety. In contrast, the 9-amino substituent profoundly diminished the apparent extent of tissue distribution, as indicated by the magnitude of Vz (7.7 liters/kg), effecting an enhanced rate of elimination (t1/2,z, 1.4 h). Comparison of the CL of CA and its two derivatives provided an inaccurate indication of drug elimination due to the influence of their unusually large Vz values. For these compounds, the relative ease of elimination from the body was best represented by mean residence times, which were 0.55, 7.24, and 11.2 h for AC, CA, and MC, respectively. Intact lactone plasma levels achieved after dosing with the lactone form of CA and its 9-amino and 10,11-methylenedioxy derivatives exceeded the far less active carboxylate at all times. In summary, these studies indicate that considerable alterations in pharmacokinetic behavior result from structural modification of the A ring of CA.