Dataset Information

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

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.

SUBMITTER: Wiebe ST

PROVIDER: S-EPMC7716890 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wiebe Sabrina T ST Giessmann Thomas T Hohl Kathrin K Schmidt-Gerets Sven S Hauel Edith E Jambrecina Alen A Bader Kerstin K Ishiguro Naoki N Taub Mitchell E ME Sharma Ashish A Ebner Thomas T Mikus Gerd G Fromm Martin F MF Müller Fabian F Stopfer Peter P

Clinical pharmacokinetics 20201201 12

<h4>Background and objective</h4>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 ...[more]

PMID: 32504272

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Project description:PurposeProbe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH.MethodsRosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate.ResultsFor rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive.ConclusionsThese data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.

Dataset Information

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

Publications

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

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