Irinotecan (CPT-11) is a prodrug of the topoisomerase I inhibitor SN-38 used in the treatment of metastatic carcinomas of the colon or rectum. The clinical utility of this drug is hindered by debilitating side effects, most notably, severe gastrointestinal toxicity, which affects up to 40% of patients. Although the accumulation of SN-38 in intestinal enterocytes, following biliary secretion and microbial metabolism of its glucuronide metabolite, is believed to be a critical preceding event to CPT-11-induced toxicity, the transport mechanism involved in this process remains incompletely understood. Here, we tested the hypothesis that the organic anion transporting polypeptide OATP2B1 is an intestinal uptake transporter of SN-38 and a critical determinant of CPT-11-induced toxicity. Mice with Oatp2b1 deficiency experienced milder diarrhea and reduced changes in their intestine length, a known injury marker, compared to wild-type mice when subjected to CPT-11 treatment. These observations were confirmed by a histological examination indicating that damage to intestinal enterocytes was more severe in wild-type mice. The phenotypic alterations in Oatp2b1-deficient mice occurred without substantial changes in measures of systemic exposure to the parent drug, SN-38, or its glucuronide conjugate. Collectively, our study indicates that plasma concentrations of SN-38 are a poor predictive biomarker of CPT-11-induced gastrointestinal toxicity and provides an incentive for the future development of intervention strategies aimed at increasing the tolerance to this clinically important drug with the use of OATP2B1 inhibitors.

Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available indicating that certain SLC family members contribute to the cellular accumulation of small molecule cancer drugs in sites of injury and contribute to unwanted toxicity to normal tissue. The present review aims to provide an overview of the toxic effects of commonly used chemotherapy drugs that are associated with SLC-mediated transport, how these associations have been derived, what ensuing intervention strategies have been explored, and how the investigation of these phenomena might change in the near future with the availability of increasingly sophisticated and innovative models and techniques. It is expected that this rapidly emerging field continues to contribute to filling our gaps in knowledge and will aid in the development of interventions aimed at preventing debilitating side effects of cancer drugs and improving quality of life.

Dose-dependent effects of cedazuridine on oral decitabine pharmacokinetics.

PurposeRibociclib is a CDK4/6 inhibitor used to treat HR+/HER2- breast cancer. Despite regulatory documents suggesting that ribociclib may inhibit both CYP3A and OATP1B-type transport in vitro, it is unclear whether CDK4/6 inhibitors interact with these mechanisms in vivo. Based on two cases of severe rhabdomyolysis in patients taking a CDK4/6 inhibitor and simvastatin, a CYP3A and OATP1B substrate, we tested the hypothesis that CDK4/6 inhibitors may precipitate drug-drug interactions through these mechanisms.MethodsWe assessed the ability of CDK4/6 inhibitors to inhibit CYP3A and OATP1B-type transporters. Based on these data, we performed pharmacokinetic studies and toxicity assessments to determine whether ribociclib is a substrate or inhibitor of OATP1B-type transport in vivo.ResultsRibociclib inhibited the metabolism of triazolam, a CYP3A probe, in vivo. Additionally, CDK4/6 inhibitors inhibited OATP1B-type transporters in vitro. However, ribociclib, the most potent OATP1B inhibitor, did not influence the pharmacokinetics or pharmacodynamics of the OATP1B substrates CDCA-24G or paclitaxel. Furthermore, Oatp1b2 deficiency did not alter the pharmacokinetics of ribociclib.ConclusionOur findings suggest that clinically significant OATP1B-mediated interactions are not anticipated with CDK4/6 inhibitors, either as victims or perpetrators, which supports ongoing clinical trials investigating the co-administration of CDK4/6 inhibitors with OATP1B substrates and inhibitors.

Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available, indicating that certain SLC family members contribute to the cellular accumulation of small-molecule cancer drugs at sites of injury and to unwanted toxicity in normal tissues. The present review aimed to provide an overview of the toxic effects of commonly used chemotherapy drugs that are associated with SLC-mediated transport, how these associations have been derived, what ensuing intervention strategies have been explored, and how the investigation of these phenomena might change in the near future with the availability of increasingly sophisticated and innovative models and techniques. It is expected that this rapidly emerging field continues to contribute to filling our gaps in knowledge and will aid in the development of interventions aimed at preventing debilitating side effects of cancer drugs and improving the quality of life. SIGNIFICANCE STATEMENT: Toxicities associated with small-molecule chemotherapeutics can be debilitating or even life-threatening and pose a burden on the healthcare system. Improving our understanding of the initiating transporter-mediated mechanisms of these side effects is crucial to the development of preventative or treatment strategies.

Tissue distribution of radiolabeled decitabine following oral administration.

Paclitaxel (Taxol) is a widely used anticancer agent that undergoes extensive hepatic metabolism and that causes a debilitating, dose-limiting peripheral neurotoxicity. We previously reported that the uptake of paclitaxel in hepatocytes and dorsal root ganglion neurons, the site of injury within the nervous system, is mediated by the organic anion transporting polypeptides OATP1B1 and OATP1B3 (Oatp1b2 in rodents), transporters that are highly sensitive to pharmacological inhibition. To facilitate future screens of chemical libraries to identify modulators and imaging-based drug distribution studies, we explored the utility of PB-Gly-Taxol and PB-GABA-Taxol, derivatives of paclitaxel linked to the coumarin-derived fluorophore Pacific Blue, as in vitro and in vivo substitute biomarker probes of paclitaxel. Transport studies in transfected HEK293 cells revealed efficient uptake of these PB-taxoids by human and murine OATP1B/Oatp1b-type transporters, with up to 100-fold increases in uptake relative to values observed in vector control cells, and inhibition of this transport by known inhibitors. Although cell viability assays demonstrated lower cytotoxicity of both PB-taxoids (IC50: 13~80 nM) against a panel of breast cancer cell lines, ensuing investigations confirmed their ability to induce peripheral neurotoxicity phenotypes in mice (p < 0.05), in an Oatp1b2-dependent manner, to the same extent as paclitaxel. These findings imply that PB-taxoids mimic the transport and toxicokinetic features of paclitaxel, and these agents thus offer potential as fluorescent imaging tools for exploring drug-drug interaction liabilities and paclitaxel-related toxicity profiles that involve OATP1B/Oatp1b-type transporters.