ArticlePharmacology research & perspectives2020
Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats.
Article in Pharmacology research & perspectives, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 29 citations in OpenAlex.
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- Regional distribution of unbound eletriptan and sumatriptan in the CNS and PNS in rats: implications for a potential central action.The journal of headache and pain · 2024Article
- Development of a 2D-QSAR Model for Tissue-to-Plasma Partition Coefficient Value with High Accuracy Using Machine Learning Method, Minimum Required Experimental Values, and Physicochemical Descriptors.European journal of drug metabolism and pharmacokinetics · 2023Article
- Physiologically Based Pharmacokinetic Model of Brain Delivery of Plasma Protein Bound Drugs.Pharmaceutical research · 2023Article
- Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans.European journal of drug metabolism and pharmacokinetics · 2022Article
- Current Chemical, Biological, and Physiological Views in the Development of Successful Brain-Targeted Pharmaceutics.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood-Brain Barrier.Neurochemical research · 2022Article
- Free Drug Theory - No Longer Just a Hypothesis?Pharmaceutical research · 2022Article
- Effects of membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver of drugs: A microdialysis study in rats.Pharmacology research & perspectives · 2021Article
- Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats.Pharmacology research & perspectives · 2020Article
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Authors and funding
22 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In clinical pharmacology, the free drug hypothesis has been widely applied in the interpretation of the relationship between pharmacokinetics and pharmacodynamics (PK/PD). The free drug hypothesis assumes that the unbound drug concentration in blood is the same as that in the site of action at steady state. The objective of this study is to demonstrate whether the free drug hypothesis is universally applicable for all drugs. The unbound concentrations of the 18 compounds in blood and in brain interstitial fluids (ISF) at steady state following constant intravenous infusion were simultaneously monitored up to 6 hours via in vivo microdialysis technique. Based on the permeability and efflux ratio (ER), the test compounds can be divided into two classes. Class I includes the compounds with good membrane permeability that are not substrates of efflux transporters (eg, P-gp, BCRP, and MRPs), whereas Class II includes the compounds that are substrates of efflux transporters. The steady-state unbound drug concentrations in blood, brain, and CSF are quantitatively very similar for Class I compounds, whereas the steady-state unbound concentrations in the brain and CSF are significantly lower than those in blood for Class II compounds. These results strongly suggest that the free drug hypothesis is not universal for all drugs but is only applicable for drugs with good permeability that are not substrates of efflux transporters.
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