Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Bosentan (Tracleer®) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with ALT, AST and DILI. After adjusting for BMI, CYP2C9*2 was the only polymorphism associated with ALT, AST and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; OR 95% CI = 2.29 - ∞, P = 0.003, respectively). Bosentan metabolism in vitro by CYP2C9*2 was significantly reduced compared to CYP2C9*1 and was comparable to CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

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.

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