Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

Abstract

Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation

“…In humans, OATP1B1 [ SLCO1B1 ] and OATP1B3 [ SLCO1B3 ] (collectively referred to as OATP1B hereafter) are partially redundant transporters that are highly expressed on the sinusoidal membrane of hepatocytes and play key roles in the hepatic uptake of drugs [ 43 , 44 , 45 ]. Inhibition of OATP1B can lead to defective elimination, result in increases in plasma concentration of drugs that are substrates of these transporters, delayed clearance, and ultimately increase the risk of therapy-related side effects [ 45 , 46 ]. Both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines require under certain conditions that in vitro studies are performed to evaluate whether investigational new drugs are potential substrates or inhibitors of OATP1B [ 47 , 48 ].…”

Inhibition of organic cation transporter 3 activity by tyrosine kinase inhibitors

“…In particular, some tyrosine kinase inhibitors (TKIs), like the Bcr‐Abl inhibitors imatinib, dasatinib and nilotinib, the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib, and the multi‐kinase inhibitors sunitinib and sorafenib, inhibit in vitro OCT3 activity, at concentrations thought to be reached in vivo for at least nilotinib, thus supporting a potential clinical relevance of these effects [14]. Whether other TKIs can also behave as inhibitors and/or substrates for OCT3 is however unknown, but likely deserves interest owing to the current development of TKIs as a leading pharmacological class for various therapeutic indications, to the role that transporters play in TKI pharmacokinetics and activity [15,16] and to the fact that some TKIs like abemaciclib have been clinically shown to increase exposure to the OCT3 substrate metformin [17]. To get insights about this point in the present study, we have analyzed the interactions of OCT3 with 25 TKIs, targeting various tyrosine kinases and regulatory‐approved ( n = 23) or under clinical development ( n = 2).…”

Interactions of Anti-COVID-19 Drug Candidates With Hepatic Transporters May Cause Liver Toxicity and Affect Drug Metabolism

“…Although with somewhat different selectivities and specificities, these transporters are responsible for the hepatocellular uptake and elimination of a wide variety of drugs and toxic compounds from the blood stream. Inhibition of these transporters causes an increase in blood retention and general toxicity of many clinically applied agents [17][18][19][20] and Figure 1.…”