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

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Clinical Pharmacology

Background:

• A novel cocktail of digoxin, furosemide, metformin, and rosuvastatin was developed to study drug transporter interactions.
• This cocktail was optimized to prevent mutual interactions between the probe drugs, which represent key drug transporters.

Purpose of the Study:

• To investigate the impact of four common drug transporter inhibitors on the pharmacokinetics of the probe drugs in the cocktail.
• To validate the drug transporter cocktail as a tool for assessing drug-drug interactions in clinical trials.

Main Methods:

• A randomized, open-label, crossover trial was conducted in 45 healthy male subjects.
• Subjects received the cocktail alone or with single oral doses of rifampin, verapamil, cimetidine, or probenecid.
• Plasma and urine concentrations of probe drugs were measured using validated LC-MS/MS assays.

Main Results:

• Rifampin significantly increased rosuvastatin exposure (AUC0-tz by 248%, Cmax by 1025%).
• Probenecid increased furosemide exposure (AUC0-tz by 172%, Cmax by 23%).
• Cimetidine reduced metformin renal clearance by 26%; verapamil's effect on digoxin was less pronounced than anticipated.

Conclusions:

• The drug transporter cocktail demonstrated sensitivity and specificity in detecting known drug-drug interactions.
• The validated cocktail is a reliable tool for evaluating transporter-mediated drug-drug interactions during drug development.
• Results align with existing in vitro and clinical data on drug interactions.