Pharmacokinetic Drug-Drug Interaction Study to Identify Biomarkers of Kidney Transporters

The objective of this study is to confirm the feasibility of using a panel of endogenous substrates/metabolites as a robust biomarker of OCTs and OATs by conducting a controlled, comprehensive clinical drug-drug interaction study in healthy adult volunteers. Metformin and furosemide will be used as probe drugs for OCTs and OATs, respectively; cimetidine and probenecid will be used as corresponding inhibitors. Results from this study will validate this novel approach, which will be extended to children by collaborators at Children's Mercy Hospital in Kansas City, MO.

Study Overview

• Status: Completed
• Conditions: Interaction; Endogenous Biomarkers
• Intervention / Treatment: Drug: MetFORMIN Oral Solution; Drug: Cimetidine 400 MG; Drug: Furosemide Oral Liquid Product; Drug: Probenecid 500 MG

Detailed Description

The kidneys are major organs responsible for the excretion of both endogenous and exogenous compounds, the latter including drugs and other xenobiotics. Excretion occurs via passive or active processes, the latter involving transporters such as organic cation transporters (OCTs) and organic anion transporters (OATs). Inhibition of these transporters, coupled with the large interindividual variability in transporter expression, can lead to toxic accumulation of compounds/xenobiotics cleared primarily by this route. During drug discovery and development, if in vitro evidence suggests renal transporters mediate excretion of a new chemical entity, the Food and Drug Administration recommends conducting a controlled clinical study to evaluate potential risks. These time-consuming and expensive clinical studies routinely involve adult participants and known substrates of renal transporters. However, such studies are not always feasible in children due to the enhanced potential for toxicities. This limitation led to the hypothesis that endogenous substrates could be used as surrogates, or biomarkers, of individual renal transporter function.

Endogenous OCT substrates, such as 1-methyladenosine (m1A) and 1-methylnicotinamide (MNA), as well as OATs, such as homovanillic acid (HVA) and pyridoxic acid (PDA), are promising biomarkers of renal transporters in adults. However, using one or few such endogenous substrates can be misleading due to factors other than variability in specific renal transporter function. We propose to address this knowledge gap by using a panel of endogenous substrates/metabolites that recently has been identified as a robust biomarker of rodent Octs and Oats. Validation of these substrates/metabolites as biomarkers of OCTs and OATs in humans, both adults and children, will aid in the development of physiologically-based pharmacokinetic models that can be used to predict renal transporter-mediated xenobiotic excretion, drug-drug interactions, and toxicity in children.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Spokane, Washington, United States, 99202
      • Washington State University College of Pharmacy and Pharmaceutical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Are from 18-65 years old and healthy

• Are not taking any medications (prescription and non-prescription) or dietary/herbal supplements that can interfere with your ability to eliminate the study drugs from your body
• Are willing to stop taking dietary/herbal supplements and citrus juices for several weeks
• Are willing to stop consuming caffeinated beverages or other caffeine-containing products the evening before and the morning of the first day of each study arm
• Are willing to stop drinking alcoholic beverages for at least 1 day prior to any study day and during the study day
• Are willing to use an acceptable method of birth control that does not include oral contraceptive pills or patches (such as abstinence, copper IUD, condom) throughout your participation in the study and for at least 3 weeks after you last take the study drugs
• Have the time to participate

Exclusion Criteria:

• Are under 18 or over 65 years old
• Smoke/vape/chew tobacco products
• Use cannabis products, including marijuana, hemp, and other THC- and CBDcontaining products• Are taking medications or dietary/herbal supplements that can interfere with your ability to eliminate the study drugs from your body
• Have a chronic illness such as (but not limited to) kidney disease, liver disease, diabetes mellitus, high blood pressure, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS
• Have a hematologic (blood) disorder
• Have a history of drug or alcohol addiction or major psychiatric illness
• Have a history of allergy to metformin, cimetidine, furosemide, or probenecid
• Are pregnant, nursing, or plan to become pregnant within 3 weeks after participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1A: metformin alone (baseline); Arm 1A will consist of administration of a single dose of metformin (50 mg) by mouth as a liquid to 16 subjects (8 males, 8 females). Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 2A and 2B. A washout of at least 7 days will occur between Arm 1A and Arm 1B.	Drug: MetFORMIN Oral Solution; liquid; Other Names: Riomet
Experimental: Arm 1B: metformin + cimetidine; Arm 1B will consist of administration of a single oral dose of cimetidine (400 mg) with water by mouth. One hour later, metformin (50 mg) will be administered by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 2A and 2B. A washout of at least 7 days will occur between Arm 1B and Arm 2A.	Drug: MetFORMIN Oral Solution; liquid; Other Names: Riomet; Drug: Cimetidine 400 MG; tablet; Other Names: Tagamet
Experimental: Arm 2A: furosemide alone (baseline); Arm 2A will consist of administration of a single dose of furosemide (5 mg) by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. A washout of at least 7 days will occur between Arm 2A and Arm 2B.	Drug: Furosemide Oral Liquid Product; oral solution; Other Names: Lasix
Experimental: Arm 2B: furosemide + probenecid; Arm 2B will consist of administration of a single oral dose of probenecid (1,000 mg) with water by mouth. One hour later, furosemide (5 mg) will be administered by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 1A and 1B. A washout of at least 7 days will occur between Arm 2B and Arm 1A.	Drug: Furosemide Oral Liquid Product; oral solution; Other Names: Lasix; Drug: Probenecid 500 MG; tablet; Other Names: Probalan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metformin Area Under the Concentration vs. Time Curve (AUC)	baseline metformin area under the concentration vs. time curve (AUC)	0-24 hours
Metformin AUC in Presence of Cimetidine	Metformin area under the concentration vs. time curve (AUC) in presence of cimetidine	0-24 hours
Metformin Maximum Concentration (Cmax)	baseline metformin maximum concentration (Cmax)	0-24 hours
Metformin Cmax in Presence of Cimetidine	metformin Cmax in the presence of cimetidine	0-24 hours
Metformin Renal Clearance (CLr)	baseline metformin renal clearance (CLr)	0-24 hours
Metformin CLr in Presence of Cimetidine	metformin CLr in the presence of cimetidine	0-24 hours
Furosemide Area Under the Concentration vs. Time Curve (AUC)	baseline furosemide area under the concentration vs. time curve (AUC)	0-24 hours
Furosemide AUC in Presence of Probenecid	furosemide AUC in the presence of probenecid	0-24 hours
Furosemide Renal Clearance (CLr)	baseline furosemide renal clearance (CLr)	0-24 hours
Furosemide CLr in Presence of Probenecid	furosemide CLr in the presence of probenecid	0-24 hours

Collaborators and Investigators

• Sponsor: Washington State University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Morrissey KM, Stocker SL, Wittwer MB, Xu L, Giacomini KM. Renal transporters in drug development. Annu Rev Pharmacol Toxicol. 2013;53:503-29. doi: 10.1146/annurev-pharmtox-011112-140317. Epub 2012 Nov 8.
• US Food and Drug Administration. Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
• Shen H, Holenarsipur VK, Mariappan TT, Drexler DM, Cantone JL, Rajanna P, Singh Gautam S, Zhang Y, Gan J, Shipkova PA, Marathe P, Humphreys WG. Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects. J Pharmacol Exp Ther. 2019 Jan;368(1):136-145. doi: 10.1124/jpet.118.252643. Epub 2018 Oct 25.
• Miyake T, Mizuno T, Takehara I, Mochizuki T, Kimura M, Matsuki S, Irie S, Watanabe N, Kato Y, Ieiri I, Maeda K, Ando O, Kusuhara H. Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters. Drug Metab Dispos. 2019 Nov;47(11):1270-1280. doi: 10.1124/dmd.119.087262. Epub 2019 Sep 11.
• Naji-Talakar S, Sharma S, Martin LA, Barnhart D, Prasad B. Potential implications of DMET ontogeny on the disposition of commonly prescribed drugs in neonatal and pediatric intensive care units. Expert Opin Drug Metab Toxicol. 2021 Mar;17(3):273-289. doi: 10.1080/17425255.2021.1858051. Epub 2021 Jan 20.
• Feng B, Varma MV. Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions. J Clin Pharmacol. 2016 Jul;56 Suppl 7:S110-21. doi: 10.1002/jcph.702.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2022
• Primary Completion (Actual): July 22, 2023
• Study Completion (Actual): July 22, 2023

Study Registration Dates

• First Submitted: May 4, 2022
• First Submitted That Met QC Criteria: May 4, 2022
• First Posted (Actual): May 9, 2022

Study Record Updates

• Last Update Posted (Actual): August 8, 2025
• Last Update Submitted That Met QC Criteria: August 6, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Kidney Transporter
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Gastrointestinal Agents; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Membrane Transport Modulators; Cytochrome P-450 Enzyme Inhibitors; Diuretics; Natriuretic Agents; Sodium Potassium Chloride Symporter Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Ulcer Agents; Uricosuric Agents; Histamine H2 Antagonists; Metformin; Furosemide; Probenecid; Cimetidine
• Other Study ID Numbers: 19163; R01HD081299 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No