THE TRANSFORMATION OF IRINOTECAN (CPT-11) TO ITS ACTIVE METABOLITE SN-38 BY HUMAN LIVER-MICROSOMES - DIFFERENTIAL HYDROLYSIS FOR THE LACTONE AND CARBOXYLATE FORMS

Irinotecan (CPT-11) is a new camptothecine derivative presently in dev elopment for the treatment of several advanced malignancies. It is con verted in vivo to a highly potent metabolite, SN-38, by carboxylestera ses. All camptothecine derivatives undergo lactonolysis in a pi-I-depe ndent reversible manner, generating inactive carboxylate forms. We hav e investigated in vitro the kinetics of transformation of CPT-11 to SN -38 by human liver microsomes originating from several donors. Microso mes from seven livers were studied individually or as a pooled prepara tion. CPT-11, either in its lactone or its carboxylate form, was added at a range of concentrations. The SN-38 formed was measured by HPLC w ith fluorometric detection. In the deacylation-limited carboxylesteras e reaction, the linear steady-state kinetics between 10 and 60 min wer e determined. At all concentrations of CPT-11, the steady-state veloci ty of SN-38 formation as well as the intercept concentrations of SN-38 were about 2-fold higher when the substrate was under the lactone for m than under the carboxylate form. We estimated the values (+/-SD) of K'(m), and V-max to be 23.3+/-5.3 mu M and 1.43+/-0.15 pmol/min/mg for the lactone and 48.9+/-5.5 mu M and 1.09+/-0.06 pmol/min/mg for the c arboxylate form of CPT-11, respectively. We conclude that the greater rate of conversion of CPT-11 lactone may contribute to the plasma pred ominance of SN-38 lactone observed in vivo. The inter-individual varia tion of SN-38 formation was relatively high (ratio of 4 between extrem e values) but no large age- or gender-related differences were seen. T he effect of twelve drugs of different therapeutic classes (antibiotic s, antiemetics, antineoplastics, antidiarrhoeics, analgesics), which c ould be administered in association with irinotecan in the clinical se tting, was evaluated in this system (drug concentration: 100 mu M; CPT -11 lactone concentration: 10 mu M). Loperamide and ciprofloxacine whe re the only drugs exerting a weak inhibition of CPT-11 conversion to S N-38.