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.

Figure 1.. Interplay of enzymes and transporters in trabectedin-mediated hepatotoxicity

Panel A. Trabectedin is metabolized by Cyp3a and both parent and metabolites are substrates for P-gp, Mrp2 and Mrp3. Pretreatment with dexamethasone, a CYP3a inducer, reduced hepatotoxicity, suggesting that CYP3A was protective. Hepatoprotection from trabectedin-mediated cytotoxicity in rat sandwich-cultured hepatocytes by dexamethasone treatment was attributed to enhanced metabolism and biliary excretion due to protein induction of Cyp3a and Mrp2, respectively, although the anti-inflammatory effect of dexamethasone could have contributed to the effect as well (3). Panel B. In Mdr1a/1b/Mrp2−/− mice, hepatotoxicity was severe, with liver transaminase levels >100-fold relative to the wild-type treated mice (2). This finding suggested that transporters are pivotal in protecting the cell by removing hepatotoxicant(s). Panel C. Only mild hepatotoxicity was observed in Cyp3a/Mdr1a/1b/Mrp2−/− mice, highlighting the importance of Cyp3a-generated metabolites as hepatotoxicants and not trabectedin itself. Loss-of-function of two transporters (e.g., Mrp2 and Mrp3; P-gp and Mrp2) caused severe hepatotoxicity, whereas the loss of one efflux pathway only produced a modest insult (2).

Figure 2:. Mechanisms of regulation of transporter gene expression, post-translational modification and intracellular distribution.

Examples of transporters affected by specific regulatory pathways include Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Protein 2 (MRP2), Organic Cation Transporter 2 (OCT2), Organic Anion Transporter 1 (OAT1) and OAT3.