Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

Abstract

Drug transporters are present in various tissues and have a significant role in drug absorption, distribution, and elimination. The International Transporter Consortium has identified 7 transporters of increasing importance from evidence of clinically significant transporter-mediated drug-drug interactions. The transporters are P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter 2, organic anion transporters (OAT) 1, and OAT3. Decision trees were created based on in vitro experiments to determine whether an in vivo transporter-mediated drug-drug interaction study is needed. Phenotyping is a methodology that evaluates real-time in vivo transporter activity, whereby changes in a probe substrate or probe inhibitor reflect alternations in the activity of the specified transporter. In vivo probe substrates and/or probe inhibitors have been proposed for each aforementioned transporter. In vitro findings and animal models provide the strongest evidence regarding probe specificity. However, such findings have not conclusively correlated with human phenotyping studies. Furthermore, the extent of contribution from multiple transporters in probe disposition complicates the ability to discern if study findings are the result of a specific transporter and thus provide a recommendation for a preferred probe for a drug transporter.

Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug‐Drug Interaction Evaluation: Perspectives From the International Transporter Consortium

“…Pitavastatin, rosuvastatin, and atorvastatin are widely used as clinical probe drugs for the evaluation of organic anion transporting polypeptide 1B1/1B3 (OATP1B)‐mediated DDIs, either following a clinically relevant oral dose or a microdose as part of a drug cocktail ( Figure and Table ). Although considered as OATP1B substrates, the aforementioned drugs as well as other proposed “probes” have been shown to be substrates for other transporters in vitro , such as OATP2B1, sodium‐taurocholate co‐transporting polypeptide (NTCP), breast cancer resistance protein (BCRP), P‐gp, organic anion transporter 3 (OAT3), and multidrug resistance‐associated protein 4 (MRP4) and MRP3 …”

An Assessment of the In Vitro Inhibition of Cytochrome P450 Enzymes, UDP-Glucuronosyltransferases, and Transporters by Phosphodiester- or Phosphorothioate-Linked Oligonucleotides

“…In addition, recent in vitro studies have shown no significant transporter inhibition for therapeutic phosphorothioate ASOs (Yu et al, 2016;Shemesh et al, 2017). Furthermore, a clinical interaction study with metformin, a drug transported by OCT1, OCT2, and multidrug and toxin extrusion MATE1/MATE2 (Momper et al, 2016), and a therapeutic phosphorothioate ASO (ISIS-113715) reported no clinical DDI (Geary et al, 2006). Given the lack of transporter interactions in literature reports, the inhibition of transporters by the generic oligonucleotides used in this study is through an unknown mechanism and the implications are unclear.…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…In vivo f t can be estimated using pharmacogenetic data in humans through mathematical modeling (Li, ). Clinical sensitive probe substrates and inhibitors for the major transporters have been reviewed (Chu et al, ; Momper, Tsunoda, & Ma, ).…”