Disease‐Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium

Abstract

Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field.

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

“…In addition to age, there are other potential factors, such as the use of comedications and inflammation that can influence transporter expression and thereby contribute to the expression variability . The impact of acute and chronic inflammation on transporter expression and activity is related to the activity of multiple proinflammatory cytokines . The exact mechanism remains unknown and may be related to various nuclear receptors and transcription factors.…”

“…The exact mechanism remains unknown and may be related to various nuclear receptors and transcription factors. Similarly, certain medications and environmental toxins could lead to activation of nuclear receptor pathway, and could, therefore, influence the transporter expression . The underlying reason for death of our tissue donors is heterogeneous and so are the exposure of drugs and environmental toxins.…”

“…43 The impact of acute and chronic inflammation on transporter expression and activity is related to the activity of multiple proinflammatory cytokines. 44 The exact mechanism remains unknown and may be related to various nuclear receptors and transcription factors. Similarly, certain medications and environmental toxins could lead to activation of nuclear receptor pathway, and could, therefore, influence the transporter expression.…”

“…Similarly, certain medications and environmental toxins could lead to activation of nuclear receptor pathway, and could, therefore, influence the transporter expression. 44,45 The underlying reason for death of our tissue donors is heterogeneous and so are the exposure of drugs and environmental toxins. Yet, despite all these inevitable differences, significant changes in the expression levels by age were still observed.…”

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

“…This is also the case for the differential transport of cyperquat/MPP + by OCT1 and OCT2 genetic variants and that of paraquat by MATE1 variants . Finally, physiological factors, such as pregnancy, infancy and old age, as well as disease parameters, including inflammation, can change transporter expression . This could influence pesticide‐transporter interactions and should thus be taken into account.…”