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Open Access 01-12-2020 | Metformin | Original Research Article

Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine

Authors: Sabrina T. Wiebe, Thomas Giessmann, Kathrin Hohl, Sven Schmidt-Gerets, Edith Hauel, Alen Jambrecina, Kerstin Bader, Naoki Ishiguro, Mitchell E. Taub, Ashish Sharma, Thomas Ebner, Gerd Mikus, Martin F. Fromm, Fabian Müller, Peter Stopfer

Published in: Clinical Pharmacokinetics | Issue 12/2020

Abstract

Background and Objective

A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug–drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics.

Methods

In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure.

Results

The results were generally in accordance with known in vitro and/or clinical drug–drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration–time curve up to the last quantifiable concentration (AUC_0–tz) by 248% and maximum plasma concentration (C_max) by 1025%. Probenecid increased furosemide AUC_0–tz by 172% and C_max by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC_0–tz unaltered, C_max + 22%).

Conclusions

Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug–drug interactions in drug development.

Clinical Trial Registration

EudraCT number 2017-001549-29.

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Title: Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine
Authors: Sabrina T. Wiebe
Thomas Giessmann
Kathrin Hohl
Sven Schmidt-Gerets
Edith Hauel
Alen Jambrecina
Kerstin Bader
Naoki Ishiguro
Mitchell E. Taub
Ashish Sharma
Thomas Ebner
Gerd Mikus
Martin F. Fromm
Fabian Müller
Peter Stopfer
Publication date: 01-12-2020
Publisher: Springer International Publishing
Keywords: Metformin
Digoxin
Verapamil
Furosemide
Rosuvastatin
Published in: Clinical Pharmacokinetics / Issue 12/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-020-00907-w

At a glance: The STEP trials

Springer Medicine

Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine

Abstract

Background and Objective

Methods

Results

Conclusions

Clinical Trial Registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusions

Clinical Trial Registration

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