Transporter-mediated drug-drug interactions. Pharmacogenomics
ABSTRACT Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed.
- SourceAvailable from: Claus-Michael Lehr
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- "Induction of P-gp can provoke elimination of P-gp substrates and decrease their bioavailability. In contrast, inhibition can increase bioavailability and amplify therapeutic efficacy, but also toxicity  . An example of inhibition is the interaction of loperamide and P-gp inhibitors at the blood–brain barrier. "
ABSTRACT: In contrast to drugs for therapeutic use, there are only few data available concerning interactions between P-glycoprotein (P-gp) and drugs of abuse (DOA). In this work, interactions between structurally diverse DOA and P-gp were investigated using different strategies. First, the effect on the P-gp ATPase activity was studied by monitoring of ATP consumption after addition to recombinant, human P-gp. Second, DOA showing an increased ATP consumption were further characterized regarding their transport across filter grown Caco-2- monolayers. Analyses were performed by luminescence and liquid chromatography-mass spectrometry, respectively. Among the nine DOA initially screened, benzedrone, diclofensine, glaucine, JWH-200, MDBC, WIN-55,212-2 showed an increase of ATP consumption in the ATPase stimulation assay. In Caco-2 transport studies, Glaucine, JWH-200, mitragynine, WIN-55,212-2 could moreover be identified as non-transported substrates, but inhibitors of P-gp activity. Thus, drug-drug or drug-food interactions should be very likely for these compoundsBiochemical Pharmacology 01/2015; 94(3). DOI:10.1016/j.bcp.2015.01.008 · 4.65 Impact Factor
African journal of pharmacy and pharmacology 10/2012; 6(38):2710-2723,. DOI:10.5897/AJPP12.487 · 0.84 Impact Factor
- "The involvement of cytochrome P450 (CYP), phase II metabolic enzymes and transport proteins in pharmaco-kinetic DDI has been detailed in various publications (Shitara et al., 2003; Müller and Fromm, 2011). The major isoforms of CYP involved in drug metabolism are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. "
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ABSTRACT: Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in blood-tissue barriers (e.g. blood-brain barrier) can limit access of small molecules to the tumour (e.g. brain tumour). Finally, transporter expression and (up)regulation in the tumour itself is known to affect local drug concentrations in the tumour tissue contributing to multidrug resistance observed for multiple anticancer agents. This review summarizes the current knowledge on: (i) small molecules as substrates of uptake and efflux transporters; (ii) the impact of transporter deficiency in knockout mouse models on plasma and tissue concentrations; (iii) small molecules as inhibitors of uptake and efflux transporters with possible consequences for drug-drug interactions and the reversal of multidrug resistance; and (iv) on clinical studies investigating the association of polymorphisms in genes encoding drug transporters with pharmacokinetics, outcome and toxicity during treatment with the small molecules.British Journal of Pharmacology 08/2011; 165(2):345-62. DOI:10.1111/j.1476-5381.2011.01618.x · 4.99 Impact Factor