Transporters in Drug Development: International Transporter Consortium Update on Emerging Transporters of Clinical Importance

Abstract

During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug development. Previously highlighted and new transporters were considered based on up‐to‐date clinical evidence of their importance in drug–drug interactions and potential for altered drug efficacy and safety, including drug–nutrient interactions leading to nutrient deficiencies. For the first time, folate transport pathways (PCFT, RFC, and FRα) were examined in‐depth as a potential mechanism of drug‐induced folate deficiency and related toxicities (e.g., neural tube defects and megaloblastic anemia). However, routine toxicology studies conducted in support of drug development appear sufficient to flag such folate deficiency toxicities, whereas prospective prediction from in vitro folate metabolism and transport inhibition is not well enough established to inform drug development. Previous suggestion of a retrospective study of intestinal OATP2B1 inhibition to explain unexpected decreases in drug exposure were updated. Furthermore, when the absorption of a new molecular entity is more rapid and extensive than can be explained by passive permeability, evaluation of the OATP2B1 transport may be considered. Emerging research on hepatic and renal OAT2 is summarized, but current understanding of the importance of OAT2 was deemed insufficient to justify specific consideration for drug development. Hepatic, renal, and intestinal MRPs (MRP2, MRP3, and MRP4) were revisited. MRPs may be considered when they are suspected to be the major determinant of drug disposition (e.g., direct glucuronide conjugates); MRP2 inhibition as a mechanistic explanation for drug‐induced hyperbilirubinemia remains justified. There were no major changes in recommendations from previous ITC whitepapers.

Physiological Characterization of the Transporter-Mediated Uptake of the Reversible Male Contraceptive H2-Gamendazole Across the Blood-Testis Barrier

“…Similarly, the functional transport characteristics of a sodium-dependent bile acid transporter were well-defined (Berk et al, 1987;Frimmer and Ziegler, 1988;Zimmerli et al, 1989) before molecular cloning experiments led to the identification of the sodiumtaurocholate co-transporting polypeptide gene (Hagenbuch et al, 1991;Hagenbuch and Meier, 1994). There are hundreds of transporters that have been identified through whole genome analysis; however, many of them are not as well-characterized as the transporters of significant clinical importance as recommended by the U.S. Food and Drug Administration and International Transporter Consortium (Giacomini et al, 2018;FDA, 2020a;FDA, 2020b;Zamek-Gliszczynski et al, 2022). For example, OATP6A1 is known to be highly and specifically expressed in the testes and in certain cancers (Suzuki et al, 2003;Lee et al, 2004;Fietz et al, 2013); however, it has yet to be functionally characterized in heterologous expression systems like OATP1B1 or OATP1B3 despite previous attempts (unpublished data).…”

Identification of Organic Anion Transporter 2 Inhibitors: Screening, Structure-Based Analysis, and Clinical Drug Interaction Risk Assessment

“…Prediction of OAT2-mediated DDI risk based on the in vitro transport inhibition data is not well established at this time due to limited direct clinical evidence . Therefore, in vivo OAT2 inhibition risk was assessed using static models, R Renal and R Hepatic , recommended for DDI risk assessment for other well-known renal (OAT1/3) and hepatic (OATP1B1/1B3) uptake transporters, respectively. ,, Within the identified inhibitors, several compounds showed an R Renal of >0.1 and R Hepatic >1.25, at their therapeutic dose suggesting the possibility of clinical DDIs with OAT2 substrates.…”

“…By combining in vitro screening and structurebased analysis, this is the first study to gain information on ligand interactions with OAT2�a transporter of emerging importance. 1,12 A single-point inhibition screen was developed using a transfected cell system, which showed time-dependent transport of cGMP and produced a high uptake ratio (∼20), enabling a good sensitivity window necessary for reliable inhibitor screening. We explored a wide drug-like chemical space, which also covers the general discovery space (Figure 1B), to identify OAT2 inhibitors and for subsequent physicochemical/structural and in silico analyses.…”

“…The goals of the current study were (i) to employ an in vitro screening approach to develop a sizable dataset of OAT2 inhibitors and non-inhibitors, (ii) to understand physicochemical drivers and structural features of the OAT2 protein–ligand interactions, and (iii) to identify potential in vivo OAT2 inhibitors that may participate in pharmacokinetic drug interactions. By combining in vitro screening and structure-based analysis, this is the first study to gain information on ligand interactions with OAT2a transporter of emerging importance. , …”

“…Interestingly, OAT2-mediated transport was found to contribute almost entirely to the active secretion of several antiviral drugs such as acyclovir, ganciclovir, and penciclovir. Currently, there are no clinically relevant inhibitors available . Functional genetic variants in SLC22A7 have not been identified yet as well, and therefore development of clinically useful probe inhibitors of OAT2 are needed to assess clinical effects of OAT2 inhibition.…”