ArticleEJNMMI research2012
Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood-brain barriers studied with (R)-[11C]verapamil positron emission tomography.
Article in EJNMMI research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Region-independent active CNS net uptake of marketed HFrontiers in cellular neuroscience · 2024Article
- Understanding the Blood-Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics.Clinical pharmacology and therapeutics · 2022Review
- Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2022Article
- Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood-Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery.Pharmaceutics · 2019Article
- Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy.International journal of molecular sciences · 2019Review
- In Vivo Monitoring for Regional Changes of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Pilocarpine-Induced Epileptic Rat Brain by Small-Animal PET.Scientific reports · 2017Article
- In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy.Molecular psychiatry · 2016Article
- The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1.Pharmacology research & perspectives · 2015Article
- Role of (drug) transporters in imaging in health and disease.Drug metabolism and disposition: the biological fate of chemicals · 2014Review
- A proposed role for efflux transporters in the pathogenesis of hydrocephalus.Croatian medical journal · 2014Review
- Advances in PET imaging of P-glycoprotein function at the blood-brain barrier.ACS chemical neuroscience · 2013Review
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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backgroundThis study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET).
methodsData obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood-brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated.
resultsOur model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment.
conclusionsUsing NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
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