Do P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier impact morphine brain distribution?

P-glycoprotein (P-gp) is a key efflux transporter and may be involved in drug-drug interactions (DDIs) at the blood-brain barrier (BBB), which could lead to changes in central nervous system (CNS) drug exposure. Morphine is a P-gp substrate and therefore a potential victim drug for P-gp mediated DDIs. It is however unclear if P-gp inhibitors can induce clinically relevant changes in morphine CNS exposure.

Exploring K values smaller than unity in remoxipride: A physiologically-based CNS model approach highlighting brain metabolism in drugs with passive blood-brain barrier transport.

(aim): K values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). K values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed.

Next-generation biomarker discovery in Alzheimer's disease using metabolomics - from animal to human studies.

Alzheimer's disease (AD) is a complex disease driven mainly by neuronal loss due to accumulation of intracellular neurofibrillary tangles and amyloid β aggregates in the brain. The diagnosis of AD currently relies on clinical symptoms while the disease can only be confirmed at autopsy. The few available biomarkers allowing for diagnosis are typically detected many years after the onset of the disease.

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects.

Despite enormous advances in CNS research, CNS disorders remain the world's leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.Following dosing, not only the chemical properties of the drug and blood-brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects.

[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.

Background: [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate.

Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease.

Background: Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods: In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg).