Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy

Abstract

The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities.

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…The clinical relevance of these findings was subsequently validated by comparing the pharmacokinetics and toxicity profiles in patients receiving irinotecan therapy (42,43). Patients with the OATP1B1*15 genotype showed increased systemic exposure and toxicities of SN-38 compared to those with the wild-type OATP1B1 (42,43). Similar findings have been reported with patients treated with methotrexate.…”

“…Compared to the wild-type OATP1B1 (OATP1B1*1a), the OATP1B1*15 displayed reduced uptake of SN-38 (an active metabolite of irinotecan), when tested in in vitro cell line models stably expressing OATP1B1 variant proteins (25). The clinical relevance of these findings was subsequently validated by comparing the pharmacokinetics and toxicity profiles in patients receiving irinotecan therapy (42,43). Patients with the OATP1B1*15 genotype showed increased systemic exposure and toxicities of SN-38 compared to those with the wild-type OATP1B1 (42,43).…”

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

“…In fact, SLCO1B1*15, which causes reduced transport activity (23), is reported to influence the area under the plasma concentration-time curve of SN-38 and irinotecan-induced toxicity (24,25). Further studies are warranted to examine the effects of genetic polymorphisms in SLCO1B1 on the pharmacokinetics of as well as toxicity of irinotecan.…”

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

“…For example, individuals carrying SLCO1B1*15 (388A>G and 521T>C) have markedly increased plasma levels of statins and are at increased risk of developing statin-induced myopathy (6,7). SLCO1B1*15 has also been associated with life-threatening toxicities in patients treated with irinotecan (8). Moreover, 2 intronic SNPs in SLCO1B1, which are linked to each other and to 521T>C, were recently associated with increased plasma clearance and gastrointestinal toxicity of MTX (mucositis grade 3 or 4) (48).…”

“…OATP1A/1Bs therefore also present a significant factor in drug-drug interactions. Additionally, various SNPs have been identified in human SLCO1A/1B genes, especially in SLCO1B1, some of which have been associated with increased plasma levels of statins and irinotecan in patients, sometimes resulting in severe and life-threatening toxicity (6)(7)(8). Genetic variation in SLCO1A/1B genes, resulting in altered transport activity, might therefore be an important factor in interindividual variation in response to drug treatment.…”