Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients

Abstract

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C4G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6b-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6b-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6b-hydroxylation determination could help to determine the optimal dose of irinotecan.

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

“…37 Continuous generation of SN-38G allows sustained high levels of SN-38G (5-25 fold higher than SN-38) in the circulation of patients. [9][10][11][12] Hydrolysis of SN-38G by A second way by which bG activation of SN-38G differs from commonly investigated prodrug/enzyme combinations is that most activating enzymes, such as herpes simplex virus thymidine kinase for ganciclovir, cytosine deaminase for 5-FC, nitroreductase for CB1954 and carboxypeptidase G2 for ZD2767P, are expressed intracellularly because the anticancer prodrugs can readily enter transduced cells by passive or facilitated transport. Glucuronides, on the other hand, do not efficiently enter cells, resulting in poor activation of glucuronide prodrugs when bG is expressed in the cytosol of mammalian cells.…”

“…7 However, a large fraction of SN-38 is further metabolized in the liver by members of the UDP-glucuronosyltransferase 1A family to the inactive glucuronide metabolite (SN-38G). 8 The serum concentration of SN-38G can exceed the concentration of SN-38 in the circulation by up to 25-fold, [9][10][11][12] thereby reducing the exposure of tumor cells to Prodrug activating gene therapy is an investigational approach to enhance the effectiveness of cancer chemotherapy that entails delivery of an enzyme encoding gene that can catalytically convert an anticancer prodrug to a cytotoxic antineoplastic agent. 13 For example, expression of carboxyesterases in cancer cells can catalyze the hydrolysis of CPT-11 to SN-38 and enhance CPT-11 antitumor activity.…”

Clinical Observations on Associations Between the UGT1A1 Genotype and Severe Toxicity of Irinotecan

“…Many studies abroad suggest that UGT1A1 genotypes are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan (Innocenti et al, 2004;Rouits et al, 2008;EGAPP Working Group, 2009). Some indicate that the risk of leucopenia or neutropenia in CPT-11-based chemotherapy is higher as the increase on dosage, especially in those who are administrated with medium or high irinotecan doses (>125mg/m 2 ) (Hu et al, 2010).…”

Irinotecan toxicity: genes or intestinal microflora?

“…The recent work by Rouits et al evaluates the role of the polymorphisms of two enzymes involved in irinotecan metabolism: UGT1A1, responsible for glucuronisation and disposal of its active metabolite SN-38; carboxylesterase-2 (CES2), responsible for SN-38 formation. CYP3A4 activity, responsible for irinotecan transformation into the inactive compounds APC and NPC, has been indirectly estimated by urinary 6b-hydroxycortisol/cortisol ratio, and can be influenced by many ambiental factors (Rouits et al, 2008).…”

“…The recent work by Rouits et al evaluates the role of the polymorphisms of two enzymes involved in irinotecan metabolism: UGT1A1, responsible for glucuronisation and disposal of its active metabolite SN-38; carboxylesterase-2 (CES2), responsible for SN-38 formation. CYP3A4 activity, responsible for irinotecan transformation into the inactive compounds APC and NPC, has been indirectly estimated by urinary 6b-hydroxycortisol/cortisol ratio, and can be influenced by many ambiental factors (Rouits et al, 2008).As authors say, UGT1A1 variants affect only haematological toxicity. An earlier, larger trial had similar results, but was statistically significant only for the first cycle and did not correlate with necessity of dose reduction (Toffoli et al, 2006).…”