ArticleDrug metabolism and disposition: the biological fate of chemicals2015
Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- Influence of St. John's Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial.Anesthesiology · 2020Trial
- Effect of P-glycoprotein inhibition at the blood-brain barrier on brain distribution of (R)-[British journal of clinical pharmacology · 2017Trial
- Central nervous system antituberculosis drug exposures in a rabbit model of tuberculous meningitis.Antimicrobial agents and chemotherapy · 2026Article
- R5 and R7 positions on fluoroquinolone scaffolds drive F-actin filament disruption.Scientific reports · 2026Article
- St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.Clinical and translational science · 2024Article
- Performance and Sensitivity of [Molecular pharmaceutics · 2024Article
- Regulation of P-Glycoprotein in the Brain.International journal of molecular sciences · 2022Review
- Transport Mechanisms at the Blood-Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs.Pharmaceutics · 2022Review
- Successful Prediction of Human Steady-State Unbound Brain-to-Plasma Concentration Ratio of P-gp Substrates Using the Proteomics-Informed Relative Expression Factor Approach.Clinical pharmacology and therapeutics · 2021Article
- Electrophysiological Biomarkers in Genetic Epilepsies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit.Frontiers in cellular neuroscience · 2021Review
- Phase 0/microdosing approaches: time for mainstream application in drug development?Nature reviews. Drug discovery · 2020Review
- Pharmacokinetic Principles and Their Application to Central Nervous System Tumors.Pharmaceutics · 2020Review
- Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model withJournal of nuclear medicine : official publication, Society of Nuclear Medicine · 2020Article
- Physiologically-Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug-Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations.Clinical pharmacology and therapeutics · 2020Review
- Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2020Article
- Review
- Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches.Clinical pharmacology and therapeutics · 2018Article
- Metabolism of SKLB-TB1001, a Potent Antituberculosis Agent, in Animals.Antimicrobial agents and chemotherapy · 2018Article
- Breaking Bad: the Structure and Function of the Blood-Brain Barrier in Epilepsy.The AAPS journal · 2017Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Permeability-glycoprotein (P-glycoprotein, P-gp), an efflux transporter at the human blood-brain barrier (BBB), is a significant obstacle to central nervous system (CNS) delivery of P-gp substrate drugs. Using positron emission tomography imaging, we investigated P-gp modulation at the human BBB by an approved P-gp inhibitor, quinidine, or the P-gp inducer, rifampin. Cerebral blood flow (CBF) and BBB P-gp activity were respectively measured by administration of (15)O-water followed by (11)C-verapamil. In a crossover design, healthy volunteers received quinidine and 11-29 days of rifampin treatment during different study periods. CBF and P-gp activity was measured in the absence (control; prior to quinidine treatment) and presence of P-gp modulation. At clinically relevant quinidine plasma concentrations, P-gp inhibition resulted in a 60% increase in (11)C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of (11)C-radioactivity. Furthermore, the magnitude of BBB P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Although our findings demonstrated that quinidine did not completely inhibit P-gp at the human BBB, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. Rifampin treatment induced systemic CYP3A metabolism of (11)C-verapamil; however, it reduced the ER by 6%. Therefore, we conclude that rifampin, at its usual clinical dose, cannot be used to induce P-gp at the human BBB to a clinically meaningful extent and is unlikely to cause inadvertent BBB-inductive drug interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.