Membrane transporters in drug development

Abstract

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling.

Quantitative Targeted Proteomics for Membrane Transporter Proteins: Method and Application

“…Drug transporters along with other ADME-related proteins, such as cytochrome P450 and phase II enzymes, play a pivotal role in defining the disposition of xenobiotics and their metabolites (1). Prediction of human pharmacokinetics (PK) remains an active and challenging area in drug discovery and development, and, as a result, various in vitro and in vivo preclinical models, such as physiological-based pharmacokinetics (PBPK) modeling, have been investigated for their capability to predict human parameters.…”

Amino Acid Transporters in Drug Discovery

“…As stated in the introduction, the International Transporter Consortium and FDA gave recommendations and guidelines for studying interactions of transporters with drugs (Giacomini et al, 2010). In particular, the pioneer research area of drug discovery and design is represented by identification of new targets of side effects.…”

“…The assumption that the majority of administered drugs interact with membrane transporters located at the boundary between the intra end extracellular environment, became accepted over the years and now is well established (DeGorter et al, 2012;Giacomini et al, 2010;Han, 2011;Huang et al, 2008;Nakanishi and Tamai, 2011). Noteworthy, the brush border epithelia of intestine and kidney tubules have a very large surface in contact with the external environments from which drugs are absorbed after oral administration or reabsorbed after glomerular filtration.…”

“…Noteworthy, the brush border epithelia of intestine and kidney tubules have a very large surface in contact with the external environments from which drugs are absorbed after oral administration or reabsorbed after glomerular filtration. In these and in other districts, such as the Blood Brain Barrier (BBB), membrane transporters mediate delivery of most drugs influencing their efficacy (Agarwal et al, 2013;Giacomini et al, 2010;Mandery et al, 2012;Pardridge, 2012). Drugtransporter interactions play also key roles in therapeutic interventions in which inhibition of a specific transporter causes beneficial effects in human pathologies.…”

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

“…Additionally, AFB 1 and its metabolite aflatoxin B 1 -epoksitglutathione are substrates of multidrug resistance protein 1 (MRP1), although the affinity of MRP1 for AFB 1 is low [12][13][14] . BCRP substrates tend to overlap with P-gp substrates [13,15] , but no information is available concerning whether AFB 1 is a substrate of P-gp. Van Herwaarden et al [10] noted that BCRP plays an important role in the renal excretion of AFB 1 .…”