PHARMACOKINETICS OF THE 9-AMINO AND 10,11-METHYLENEDIOXY DERIVATIVES OF CAMPTOTHECIN IN MICE

Although, 20(S)-camptothecin (CA) exhibited potent cytotoxicity agains t a broad spectrum of tumor models, clinical trials with the sodium sa lt of its opened lactone ring form were discontinued due to highly var iable and severe toxicity. Recently, the 9-amino (AC) and 10,11-methyl enedioxy (MC) derivatives of CA were selected for preclinical evaluati on by the National Cancer Institute. In the present investigation, the pharmacokinetic behavior of CA, its sodium salt CA, AC, and MC in mic e was characterized using specific liquid chromatographic assays which permitted determination of the intact lactone and opened ring carboxy late 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 c omprised only 14.6% of the area under the concentration-time profile. The relative magnitudes of the total body apparent volume of distribut ion (V(z)) and terminal phase rate constant suggest that the high obse rved total plasma clearance (CL, 104 ml/min/kg) may be associated with extensive accumulation in peripheral tissue regions from which the dr ug is slowly released. In comparison. the terminal disposition phase o f 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/k g) and V(z) (694 liters/kg). This suggested that the degree of binding to tissues relative to plasma proteins was enhanced by the methylened ioxy moiety. In contrast, the 9-amino substituent profoundly diminishe d the apparent extent of tissue distribution, as indicated by the magn itude of V(z) (7.7 liters/kg), effecting an enhanced rate of eliminati on (t1/2,z), 1.4 h). Comparison of the Cl, of CA and its two derivativ es provided an inaccurate indication of drug elimination due to the in fluence of their unusually large V(z) values. For these compounds. the relative ease of elimination from the body was best represented by me an 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 w ith the lactone form of CA and its 9-amino and 10.11-methylenedioxy de rivatives exceeded the far less active carboxylate at all times. In su mmary, these studies indicate that considerable alterations in pharmac okinetic behavior result from structural modification the A ring of CA . The large differences in pharmacokinetic parameters of the potential candidates for clinical development, AC and MC, will play an importan t role in the selection of a therapeutically effective dosing regimen.