Comparative evaluation of recommendations for preclinical studies of transporter-mediated drug–drug interactions

Scientific relevance. Sound recommendations for preclinical studies of transporter- mediated pharmacokinetic interactions of medicinal products can help increase the likelihood of identifying potentially nephrotoxic and hepatotoxic medicinal products at the development and authorisation stages. However, overly strict requirements for the number of studies to be performed may lead to a significant increase in the cost of finished medicinal products.

Aim. The aim was to compare regulatory documents on studying transporter-mediated drug–drug interactions (DDIs).

Discussion. This review examines changes in regulatory requirements for studying DDIs in chronological order from the first guidelines that appeared in 1997. As exemplified in this article, the multiplicity of transporters and the lack of specific inhibitors pose significant challenges in assessing the role of a particular transporter in drug distribution and drug–drug interactions. This comparative review shows that extrapolating from in vitro transporter inhibition studies to in vivo pharmacokinetics can be misleading.

Conclusions. A unified approach to studying transporter-mediated DDIs will increase the likelihood of identifying potentially toxic agents at the stage of new molecule screening. At the same time, it is advisable to limit the number of in vitro and in vivo transporter studies and recommend conducting these studies only for medicinal products with a narrow therapeutic index.

1. Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol. 2008;48(6):662–70. https://doi.org/10.1177/0091270007312153

2. DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther. 2010;87(3):272–7. https://doi.org/10.1038/clpt.2009.295

3. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14. https://doi.org/10.1038/nrd3078

4. Zamek-Gliszczynski MJ, Sangha V, Shen H, Feng B, Wittmer MB, Varma MVS, et al. Transporters in drug development: International transporter consortium update on emerging transporters of clinical importance. Clin Pharmacol Ther. 2022;112(3):485–500. https://doi.org/10.1002/cpt.2644

5. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36. https://doi.org/10.1038/nrd3028

6. Iusuf D, Sparidans RW, van Esch A, Hobbs M, Kenworthy KE, van de Steeg E, et al. Organic anion-transporting polypeptides 1a/1b control the hepatic uptake of pravastatin in mice. Mol Pharm. 2012;9(9):2497–504. https://doi.org/10.1021/mp300108c

7. Vlaming ML, Pala Z, van Esch A, Wagenaar E, de Waart DR, van de Wetering K, et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res. 2009;15(9):3084–93. https://doi.org/10.1158/1078-0432.ccr-08-2940

8. Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, et al. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol. 2006;17(8):2127–35. https://doi.org/10.1681/asn.2006030205

9. Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug–drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther. 2012;340(2):393–403. https://doi.org/10.1124/jpet.111.184986

10. Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther. 2009;329(1):185–91. https://doi.org/10.1124/jpet.108.147918

11. Frymoyer A, Shugarts S, Browne M, Wu AHB, Frassetto L, Benet LZ. Effect of single-dose rifampin on the pharmacokinetics of warfarin in healthy volunteers. Clin Pharmacol Ther. 2010;88(4):540–7. https://doi.org/10.1038/clpt.2010.142

12. Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res. 2007;24(9):1720–8. https://doi.org/10.1007/s11095-007-9278-4

13. Oostendorp RL, Buckle T, Beijnen JH, van Tellingen O, Schellens JHM. The effect of Pgp (Mdr1a/1b), BCRP (Bcrp1) and Pgp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Invest New Drugs. 2009;27(1):31–40. https://doi.org/10.1007/s10637-008-9138-z

14. Chen C, Stock JL, Liu X, Shi J, Van Deusen JW, Di- Mattia DA, et al. Utility of a novel Oatp1b2 knockout mouse model for evaluating the role of Oatp1b2 in the hepatic uptake of model compounds. Drug Metab Dispos. 2008;36(9):1840–5. https://doi.org/10.1124/dmd.108.020594

15. Chu XY, Strauss JR, Mariano MA, Li J, Newton DJ, Cai X, et al. Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J Pharmacol Exp Ther. 2006;317(2):579–89. https://doi.org/10.1124/jpet.105.098665