Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease

center dot The anticancer agent irinotecan is a prodrug that is hydrolyzed by hepatic carboxylesterase to its active and toxic metabolite SN-38 and oxidized by CYP3A4 to its inactive metabolite APC. center dot Irinotecan therapy is complicated by co-administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN-38 formation. center dot Dose adjustment in cancer patients with liver disease has been recommended. WHAT THIS STUDY ADDS center dot In microsomal fractions from patients with severe hepatic dysfunction both APC and SN-38 formation were decreased due to down-regulation of CYP3A4 and carboxylesterase enzymes. Thus relative SN-38 : APC formation was preserved. center dot In some fractions the SN-38 : APC ratio was increased, thus providing a possible explanation for clinical reports of increased SN-38 exposure in some patients with liver dysfunction. center dot Close monitoring of SN-38 formation in patients with severe liver disease is warranted. AIMS Dose modification with the anticancer agent irinotecan is recommended in patients with severe liver dysfunction. This study evaluated the impact of liver disease on the relative formation of phase I products of irinotecan biotransformation in human microsomes in vitro. METHODS Microsomes from subjects with normal liver function and liver dysfunction (n = 20) were assessed for irinotecan biotransformation and the expression of cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) enzymes. RESULTS Liver disease down-regulated CYP3A4 expression (median 33% of control, range 0-126%, P < 0.05) and impaired CYP3A4-dependent oxidation of irinotecan to the inactive 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) (median 0.2, range 0-1.21 pmol mg protein-1 min-1 compared with median 0.66, range 0-2.35 in control, P < 0.01). CES-mediated hydrolysis of irinotecan to 7-ethyl-10-hydroxycamptothecin (SN-38) was also impaired in liver disease (median 8.38, range 0-20.7 pmol mg protein-1 min-1 compared with median 13.3, range 0-28.9 in control, P < 0.05). In seven of 20 liver disease microsomes neither metabolite was detected but in three the SN-38 : APC ratio was high (41-68) compared with the remaining 10 samples (ratio 11-36). CONCLUSIONS Down-regulation of CYP3A4 in liver disease decreased APC formation from irinotecan. SN-38 production was decreased and CES1 and 2 were down-regulated in most samples. However, in a subset of disease samples SN-38 production was relatively high because CYP3A4 activity was markedly impaired. This may account for clinical reports of increased SN-38 exposure in some patients with liver disease. Dose adjustments in cancer patients with liver disease who receive irinotecan are important and circulating SN-38 concentrations should be monitored closely.