ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia

Abstract

Neutropenia is a common dose-limiting toxicity associated with irinotecan treatment. Although UGT1A1 variants have been associated with neutropenia, a fraction of neutropenia risk remains unaccounted for. To identify additional genetic markers contributing to variability in irinotecan pharmacokinetics and neutropenia, a regression analysis was performed in 78 irinotecan-treated patients to analyze comprehensively three hepatic efflux transporter genes (ABCB1, ABCC1 and ABCG2). rs6498588 (ABCC1) and rs12720066 (ABCB1) were associated with increased SN-38 exposure, and rs17501331 (ABCC1) and rs12720066 were associated with lower absolute neutrophil count nadir. rs6498588 and a variant in high linkage disequilibrium are located in transcriptionally active regions or are predicted to alter transcription factor binding sites. While enhancer activity was not evident in vitro for genomic regions containing these single-nucleotide polymorphisms, rs6498588 was significantly associated with ABCC1 expression in human liver. These results suggest that genetic variation in ABCC1 and ABCB1 may contribute to irinotecan-induced neutropenia by altering expression of transporters involved in irinotecan metabolite disposition.

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

“…With an MAF of approximately 30%, this genetic variant is commonly detected in Caucasians and African Americans [ 252 ]. Clinically, UGT1A1*93 is associated with increased SN-38 AUC [ 256 ], lower neutrophil count [ 257 ], increased incidence of hematologic toxicities (including neutropenia) [ 258 , 259 ], diarrhea [ 260 ], and grade 3 vomiting [ 261 ]. Moreover, UGT1A1*93 was also part of a haplotype including variant alleles of UGT1A1*28, *60, *93, and UGT1A7*3 , which was associated with increased RR [ 262 ].…”

Drug–drug–gene interactions and adverse drug reactions

“…MRP1, for example, transports the active metabolite of irinotecan (SN-38) out of hepatocytes into the blood contributing to the well-known side effect of irinotecan induced neutropenia [44]. The reduced function variant, rs17501331, in the ABCC1 gene is associated with low incidence of neutropenia; the reverse effect was detected with the GOF variant rs6498588 in the same gene [45]. In some cases, increased activity of the MRP1 transporter can be advantageous, as seen with methotrexate hepatotoxicity where carriers of wild-type genotype of ABCC1 rs246240 (A>G) variant are at higher risk for developing methotrexate toxicity compared with carriers of reduced function alleles [46].…”

Prevalence of UGT1A1*93 and ABCC5 Polymorphisms in Cancer Patients Receiving Irinotecan-Based Chemotherapy at Al-Najaf Al-Ashraf

“…This finding was consistent with Li et al and Crona et al studies, who postulated that a polymorphism of UGT1A1*93 was a strong predictor of irinotecan induced neutropenia, that is associated with higher SN-38 AUC and lower absolute neutrophils3 counts (ANC) nadirs. (11,29) The ABCC5 transporter function was unclear until recently, in which it was found that ABCC5 transporter plays a role in the transport of cyclic nucleotides and platinum-based and nucleosidebased analog used in anticancer treatment (e.g. irinotecan and its active metabolite SN-38).…”

“…Then it is further conjugated and detoxified in the hepatic cells by UDP-glucuronosyltransferase (UGT) 1A1 and 1A9 enzyme and extrahepatic by UGT1A7 enzyme to yield its h-glucuronide, SN-38 G. (10) SN-38 and SN-38G are substrates for protein pumps, responsible for a unidirectional compound efflux from hepatocytes into bile and urine [ATP binding cassette (ABC) transporters] to be eliminated. (11) Irinotecan used in a wide range as an anticancer agent in many solid tumors because of its cytotoxic effect through the interaction with the topoisomerase I enzyme. (12) It is approved worldwide for first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic colorectal cancer and as a single agent for second-line therapy of fluorouracil refractory metastatic colorectal cancer (13) .…”

“…Recently, and after identifying the irinotecan pharmacology in many studies, a series of genes has investigated for their possible contribution to the variability in irinotecan disposition and adverse effects. (17,18) Other polymorphisms in metabolizing enzymes (UGT1A1, UGT1A7, UGT1A9, and CES) and transporters [ATP-binding cassette (ABC) and SLCO1B1] genes extensively studied in relation to pharmacodynamics and pharmacokinetics of irinotecan (11,(19)(20)(21) .…”