Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

Abstract

Key Words. P-glycoprotein • Drug interaction • Complementary and alternative medicine • CAM • Pharmacokinetics Pharmacodynamics LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.2. Describe how unwanted drug-drug interactions may lead to unexpected serious toxicity or undertreatment.3. Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s).Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported. Inhibition or induction of P-gp by coadministered drugs or food as well as herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or undertreatment. On the other hand, modulation of P-gp expression and/or activity may be a useful strategy to improve the pharmacological profile of anticancer P-gp substrate drugs. In recent years, the use of complementary and alternative medicine (CAM), like herbs, food, and vitamins, by cancer patients has increased significantly. CAM use substantially increases the risk for interactions with anticancer drugs, especially because of the narrow therapeutic window of these compounds. However, for most CAMs, it is unknown whether they affect metabolizing enzymes and/or drug transporter activity. Clinically relevant interactions are reported between St John's wort or grapefruit juice and anticancer as well as nonanticancer drugs. CAM-drug interactions could explain, at least in part, the large interindividual variation in efficacy and toxicity associated with drug therapy in both cancer and noncancer patients.

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

“…DDIs with the transporter occur because many cardiovascular drugs are substrates for and functional inhibitors of the transporter [4,7,13,14]. This is particularly problematic for cardiovascular drugs with relatively low therapeutic indexes such as antiarrhythmic drugs and oral anticoagulants because coadministration with these drugs can lead to elevated drug plasma concentrations and increased toxicity [7].…”

Overexpression of P-glycoprotein on fibroblast-like synoviocytes in refractory rheumatoid arthritis patients: a potential mechanism for multidrug resistance in rheumatoid arthritis treatment

“…Likewise, the synovium tissue expresses higher levels of P-gp mRNA in RA patients, especially in those treated with three types of DMARD (Jorgensen et al, 1995). Th1 cells also exhibit increased expression of P-gp and participate in drug resistance to sulfasalazine and bucillamine in RA patients, which suggests P-gp as an indicator of response to these two DMARDs (Marchetti et al, 2007). Consequently, we infer that P-gp is involved in drug resistance to DMARDs in RRA.…”

ABC transporters: circadian rhythms and sex-related differences

“…Beyin, plasenta, testis, lenfosit gibi dokularda lokalize olan P-gp, çeşitli kan-doku bariyerini oluşturarak ilaçların duyarlı doku ve hücrelere girişlerini sınırlandırmakta ve bu dokularda toplanmalarını azaltmaktadır. P-gp, bu hassas dokuları zararlı maddelere karşı doğal koruma fonksiyonunu gerçek-leştirirken, bir taraftan da ilaç dağılımını etkileyerek özellik-le bazı ilaçların (antipsikotik ilaçlar, HIV proteaz inhibitörleri, antineoplastik ilaçlar) terapötik etkilerini göstermelerine engel olabilir (7,9,17,18). Yapılan in vitro ve in vivo çalışma-larda P-gp inhibisyonu ve indüksiyonunun ilaç etkileşmele-rine neden olduğu gösterilmiştir.…”