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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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.• Irinotecan therapy is complicated by co-administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN-38 formation. • Dose adjustment in cancer patients with liver disease has been recommended. WHAT THIS STUDY ADDS• 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.• 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.• Close monitoring of SN-38 formation in patients with severe liver disease is warranted. AIMSDose 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. METHODSMicrosomes 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. RESULTSLiver 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). CONCLUSIONSDown-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.

The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?

“…It has also been reported that perindopril and cilazapril hydrolysis is decreased in patients with hepatic cirrhosis and hepatitis, respectively . The metabolism of irinotecan by CYP3A4 and its hydrolysis by carboxylesterases to SN‐38 was decreased in hepatic microsomes from subjects with liver dysfunction . Such decreases in metabolic activity associated with hepatic disease are expected to occur based on the location of carboxylesterase enzymes in the endoplasmic reticulum; however, an unusual finding of increased carboxylesterase 1 levels in mice (containing human‐mouse chimeric livers) infected with hepatitis C virus suggests caution in assuming hepatic infection results in reduced enzymatic activity.…”

Examination of the carboxylesterase phenotype in human liver

“…Pharmacokinetic studies have shown that considerable differences in interpatient irinotecan metabolism exist and one of the limiting factors in the efficacy of this compound is its bioactivation by CES [14]. In addition, impaired irinotecan hydrolysis in patients with chronic liver disease has been observed [15]. Furthermore, estercontaining pesticides such as pyrethroids and organophosphates (OPs) can elicit acute and developmental effects in rodents and possibly in humans [16], [17], which may be related to the hydrolytic metabolism of these compounds.…”

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

“…Up to now, data regarding the hepatic metabolism of 9-AC is limited as only one study reported the occurrence of hepatic biotransformation products without any structural information or quantification (20). The structural analog irinotecan is inactivated by hepatic cytochrome P450 (CYP) 3A4-dependent oxidation to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1piperidino] carbonyloxy-camptothecin and when CYP3A4 metabolism is affected, dose modification of irinotecan has been shown to be necessary (21). It is therefore highly probable that 9-AC is also subject to CYP-mediated biotransformation, resulting in lower plasma levels in patients, as impairment of 9-AC serum concentrations and increased clearance have already been observed in patients receiving hepatic enzymeinducing anticonvulsant medications (22).…”