The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes. Differential hydrolysis for the lactone and carboxylate forms

摘要: Irinotecan (CPT-11) is a new camptothecine derivative presently in development for the treatment of several advanced malignancies. It converted vivo to highly potent metabolite, SN-38, by carboxylesterases. All derivatives undergo lactonolysis pH-dependent reversible manner, generating inactive carboxylate forms. We have investigated vitro kinetics transformation CPT-11 SN-38 human liver microsomes originating from donors. Microsomes seven livers were studied individually or as pooled preparation. CPT-11, either its lactone form, was added at range concentrations. The formed measured HPLC with fluorometric detection. In deacylation-limited carboxylesterase reaction, linear steady-state between 10 and 60 min determined. At all concentrations velocity formation well intercept about 2-fold higher when substrate under form than form. estimated values (+/-SD) K'm Vmax be 23.3 +/- 5.3 microM 1.43 0.15 pmol/min/mg 48.9 5.5 1.09 0.06 respectively. conclude that greater rate conversion may contribute plasma predominance observed vivo. inter-individual variation relatively high (ratio 4 extreme values) but no large age- gender-related differences seen. effect twelve drugs different therapeutic classes (antibiotics, antiemetics, antineoplastics, antidiarrhoeics, analgesics), which could administered association irinotecan clinical setting, evaluated this system (drug concentration: 100 microM; microM). Loperamide ciprofloxacine where only exerting weak inhibition SN-38.