ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

Abstract

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (Pgp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.

Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology

“…In literature, administration of strong inhibitors of CYP3A4 such as azoles or diltiazem increases sirolimus trough concentrations [ 21 ], as does the co-administration of cyclosporine, a substrate and inhibitor of the p-glycoprotein [ 33 ]. In our study, irinotecan, a p-glycoprotein substrate that may compete for p-glycoprotein transport [ 32 , 34 ], was administered during a 90 min infusion in different doses (125, 200, or 240 mg/m 2 ) just prior to sirolimus intake on D1. No effect of irinotecan doses was observed on sirolimus pharmacokinetic parameters ( p > 0.05).…”

CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Are Associated with Increased Serum Coenzyme Q10 after Long-Term Supplementation in Women

“…In patients with colorectal cancer, rs2032582 GG genotype correlates with the highest P- glycoprotein expression in the tumor tissue [ 46 ]. In accordance with the ABCB1 expression, its rs2032582 polymorphism was associated with irinotecan-induced severe mucositis in metastatic colorectal cancer patients [ 47 ]. CD36 is a multi-ligand scavenger receptor whose primary function is to take up fatty acids and oxidized lipoproteins into cells [ 48 ].…”

Pharmacogenetics of Drugs Used in the Treatment of Cancers

“…Apart from metabolizing enzymes, polymorphisms within transport proteins may also affect the efficacy of irinotecan. The increased expression of ATP-binding cassette subfamily B member 1 (ABCB1, P-glycoprotein (P-gp)) participating in the biliary excretion of CPT-11 and SN-38 has been found to raise SN-38 secretion, which results in its diminished plasma levels and an enhanced risk of intestinal toxicity, decreasing at the same time the risk of neutropenia [ 93 , 94 , 95 ]. Several ABCB1 variants—including rs1128503 (1236 C/T), rs2032582 (2677 G>T/A), and rs1045642 (3435 C/T)—have been confirmed to affect P-gp expression, SN-38 plasma concentrations, and renal clearance [ 96 , 97 ].…”

“…Several ABCB1 variants—including rs1128503 (1236 C/T), rs2032582 (2677 G>T/A), and rs1045642 (3435 C/T)—have been confirmed to affect P-gp expression, SN-38 plasma concentrations, and renal clearance [ 96 , 97 ]. Riera et al [ 93 ] suggested the ABCB1 rs1128503 variant as a predictor of irinotecan-related severe gastrointestinal toxicity, especially diarrhea and mucositis. Moreover, the rs2032582 variant also seems to increase the risk of severe mucositis.…”