CYP P450 and non-CYP P450 Drug Metabolizing Enzyme Families Exhibit Differential Sensitivities towards Proinflammatory Cytokine Modulation.

Compromised hepatic drug metabolism in response to proinflammatory cytokine release is primarily attributed to downregulation of cytochrome P450 (CYP) enzymes. However, whether inflammation also affects other phase I and phase II drug metabolizing enzymes (DMEs), such as the flavin monooxygenases (FMOs), carboxylesterases (CESs), and UDP glucuronosyltransferases (UGTs), remains unclear. This study aimed to decipher the impact of physiologically relevant concentrations of proinflammatory cytokines on expression and activity of phase I and phase II enzymes, to establish a hierarchy of their sensitivity as compared with the CYPs.

Anti-tuberculosis effect of isoniazid scales accurately from zebrafish to humans.

Background And Purpose: There is a clear need for innovation in anti-tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate pharmacological findings to higher vertebrates, including humans, the internal exposure of drugs needs to be quantified and linked to observed response.

Effects of daily L-dopa administration on learning and brain structure in older adults undergoing cognitive training: a randomised clinical trial.

Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signalling in plasticity.

LUF7244, an allosteric modulator/activator of K 11.1 channels, counteracts dofetilide-induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model.

Background And Purpose: K 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of K 11.

Blood-Based Biomarkers of Quinpirole Pharmacology: Cluster-Based PK/PD and Metabolomics to Unravel the Underlying Dynamics in Rat Plasma and Brain.

A key challenge in the development of central nervous system drugs is the availability of drug target specific blood-based biomarkers. As a new approach, we applied cluster-based pharmacokinetic/pharmacodynamic (PK/PD) analysis in brain extracellular fluid (brain ) and plasma simultaneously after 0, 0.17, and 0.

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

Background And Purpose: Because biological systems behave as networks, multi-biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi-biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short- and long-term D receptor activation was evaluated using quinpirole as a paradigm compound.

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions.

Diurnal variation in the pharmacokinetics and brain distribution of morphine and its major metabolite.

The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine.

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

Purpose: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition.

Methods: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments.

Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat.

To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD).

Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.

Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp).

Prediction of methotrexate CNS distribution in different species - influence of disease conditions.

Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured.

Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion.

Online solid phase extraction with liquid chromatography-tandem mass spectrometry to analyze remoxipride in small plasma-, brain homogenate-, and brain microdialysate samples.

Remoxipride is a selective dopamine D(2) receptor antagonist, and useful as a model compound in mechanism-based pharmacological investigations. To that end, studies in small animals with serial sampling over time are needed. For these small volume samples currently no suitable analytical methods are available.

P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.

Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls.