Clinical Relevance: Drug–Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

“…They limit the intestinal uptake and the brain and fetal penetration of xenobiotics, and due to their localization in liver and kidney, they may facilitate the elimination of toxic compounds. Similarly, they can affect the pharmacologic behavior (absorption, distribution, metabolism, excretion, and toxicity) of various (anticancer) drug substrates (4).…”

Novel No-Wash Luminogenic Probes for the Detection of Transporter Uptake Activity

“…The organic anion-transporting polypeptides (OATPs) are transmembrane proteins that are members of the solute carrier (SLC) superfamily of transporters. − They include OATP1B1 and OATP1B3, which are enriched in the liver, and are responsible for the sodium-independent transport of a variety of amphipathic molecules from the blood into hepatocytes. − Transported substrates include endogenous molecules such as bile acids, hormones, and steroid conjugates, as well as xenobiotics including drugs such as methotrexate, rifampicin, and the statin family of cholesterol-lowering compounds. − OATPs play a central role in the clearance of drugs via their uptake from the hepatic portal vein. ,, Genetic polymorphisms can result in changes in the function and expression of OATPs, which may consequently lead to altered pharmacological effects, such as decreased drug efficacy, and increased risk of adverse effects. , As such, hepatic transporters are now recognized as significant contributors to the disposition, effectiveness, and adverse reactions of drugs. − Importantly, due to their roles in the ADME profiles of drugs, transporters are responsible for mediating certain drug–drug interactions (DDIs), which occur when the transport of one drug is affected by another. − For example, the coadministration of statins with cyclosporine, a potent inhibitor of OATP1B1, can result in increased blood level concentrations of the statins, which in turn may lead to dangerous myotoxic side effects . Early in vitro testing of transporter activity not only sheds insight on DDIs, but can also significantly reduce the failure rates of drugs at the clinical stage. , As a result, it is important that any involvement of transporters be determined during preclinical drug evaluation. , Accordingly, the FDA published a Draft Guidance for Industry in 2012 recommending that all drugs under investigation that are hepatically cleared be tested as substrates for OATP1B1 and OATP1B3.…”

Drug Transporters

“…Drug-induced idiosyncratic or hypersensitive reactions are a major reason for failure of new drug development and withdrawal of approved drugs from the market (Davila et al, 2007;Gunawan and Kaplowitz, 2007;Amacher, 2012). The mechanisms associated with drug-induced idiosyncratic or hypersensitive reactions are still unclear; however, evidence increasingly suggests involvement of drug transporters (Bodo et al, 2003;Glavinas et al, 2004;Marchetti et al, 2007;Morgan et al, 2010;Degorter et al, 2012).…”