Pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with antileukemic activity

Purpose. To examine the pharmacokinetic features and metabolism of calphost in C, a naturally occurring perylenequinone with potent antileukemic activi ty. Methods. HPLC-based quantitative detection methods were used to measure cal phostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(APL-EI) system were used to study the metabolis m of calphostin C. Results. An intracellular exposure level (AUC(0-6h)) of 257 mu M.h was achi eved after in vitro treatment of NALM-6 cells with calphostin C at a 5 mu M final concentration in culture medium. After intraperitoneal (i.p.) inject ion of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated C-max was 2.9 mu M, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administrat ion was rapid with an absorption half-life of 24.2 min and the estimated t( max) was 63.0 min. Calphostin C was cleared with an elimination half-life o f 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a t(max) of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metab olite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukem ic activity can be reached in mice at nontoxic dose levels. This pilot phar macokinetic study of calphostin C combined with the availability of the des cribed quantitative HPLC method for its detection in cells and plasma provi de the basis for future preclinical evaluation of calphostin C and its pote ntial as an anti-leukemic drug.