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The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.
J Pharm Sci. 2015 Sep; 104(9):3220-8.JP

Abstract

Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation.

Authors+Show Affiliations

Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.Pharmacokinetics and Non-Clinical Safety Department, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Company, Ltd., Kobe, Japan.Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25981193

Citation

Ebner, Thomas, et al. "The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail." Journal of Pharmaceutical Sciences, vol. 104, no. 9, 2015, pp. 3220-8.
Ebner T, Ishiguro N, Taub ME. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail. J Pharm Sci. 2015;104(9):3220-8.
Ebner, T., Ishiguro, N., & Taub, M. E. (2015). The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail. Journal of Pharmaceutical Sciences, 104(9), 3220-8. https://doi.org/10.1002/jps.24489
Ebner T, Ishiguro N, Taub ME. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail. J Pharm Sci. 2015;104(9):3220-8. PubMed PMID: 25981193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail. AU - Ebner,Thomas, AU - Ishiguro,Naoki, AU - Taub,Mitchell E, Y1 - 2015/05/15/ PY - 2015/02/24/received PY - 2015/04/10/revised PY - 2015/04/10/accepted PY - 2015/5/19/entrez PY - 2015/5/20/pubmed PY - 2016/5/12/medline KW - ABC transporters KW - P-glycoprotein KW - drug interaction KW - efflux pumps KW - inhibition KW - kinetics KW - organic anion transporters KW - organic anion-transporting polypeptide transporters KW - organic cation transporters SP - 3220 EP - 8 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 104 IS - 9 N2 - Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/25981193/The_Use_of_Transporter_Probe_Drug_Cocktails_for_the_Assessment_of_Transporter_Based_Drug_Drug_Interactions_in_a_Clinical_Setting_Proposal_of_a_Four_Component_Transporter_Cocktail_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(16)30102-2 DB - PRIME DP - Unbound Medicine ER -