Over four decades ago, studies began to surface indicating increases in plasma concentrations of drugs in patients and animal models of inflammation. Historically, inflammation-mediated changes in plasma drug concentrations were primarily ascribed to altered drug metabolism and plasma protein binding. However, emerging evidence has revealed that variations in the expression and activity of drug transporters also contribute to interindividual variability in drug disposition. Many therapeutic agents are transferred across epithelial membrane barriers via transporter proteins during the processes of absorption, distribution, and elimination, thus dysregulation of the transporters in inflammatory conditions can impact both the pharmacokinetics and pharmacodynamics of their substrates. Inflammation-mediated changes in the expression of numerous ATP-binding cassette efflux transporters and SLC uptake transporters have been reported in tissues of the liver, kidney, intestine, brain, and placenta. This chapter focuses on changes in the expression of members of the transporters that have been identified by the International Transporter Consortium as clinically important in drug absorption and disposition and hence drug development.lthough considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancersAlthough oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical–basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters.

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Regards

John Mathews

American Journal of Pharmacology and Pharmacotherapeutics