Role of Transporters in Drug Interactions

Drug-drug transport interactions are important in combinationtherapy with HIV protease inhibitors (117). Many protease inhibitors are substrates for and inhibitors of CYP3A4 and P-gp. Different combination effects (e.g./ intrinsic clearance of amprenavir is reduced by nelfinavir and indinavir but not saquinavir) depend on the extent to which one or both of these enzymes are affected. 

P-gp Inhibition as an Adjunct to Treating Chemotherapy-Resistant Cancers 

Recognition of the importance of drug resistance efflux pumps has motivated a number of attempts to 

The responses of these three cancer types were found to differ during clinical trials of MDR-1 inhibitors (123). For the first class, MDR-1 inhibition has had little effect on the efficacy of the cancer therapy. It appears that too many other transporters and drug resistance mechanisms are present in front-line defense organs such as kidney, liver, and intestine. For the second class, at least transiently improved responses to anticancer drugs have been seen with MDR-1 inhibitor cotherapy. However, a second relapse is seen as other transport 

In addition to mutations that alter drug uptake, several systems are known to confer bacterial drug 

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Endres CJ, Hsiao P, Chung FS, Unadkat JD. The role of transporters in drug interactions. Eur J Pharm Sci 2006 27 501-17. 

List of Clinically Relevant Substrates and Inhibitors of Pgp. Reprinted from European Journal of Pharmaceutical Sciences Official Journal of the European Federation for Pharmaceutical Sciences, Volume 27, CJ. Entires, P. Hsiao, F.S. Chung, and J.D. Unadkat, The role of transporters in drug interactions, pp. 501-517, Copyright 2006, with permission from Elsevier. 

Given the important role of transporters in ADMET and drug-drug interactions, the screening of drugs for their affinity as substrates or inhibitors of transporters should be a standard component of the ADME package in the discovery (Balani et al., 2005) and development stages. 

Figure 6.2 highlights the role of lipophilicity in the active transport of drugs. Peak values for renal clearance for these compounds occur at log D7 4 values between - 2 and 0. These values span the region where the compounds have sufficient lipophilicity to interact with the transport proteins but are not substantially reabsorbed. 

DuBuske LM The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf 2005 28 789. [PMID 16119972]... 

Kindla J, Fromm M, and Konig J (2009) In vitro evidence for the role of OATP and OCT uptake transporters in drug-drug interactions. Expert Opin Drug Metab Toxicol 5 489-500. 

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