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.

Re-evaluating the relationship between female social bonds and infant survival in wild baboons.

Over the past few decades studies have provided strong evidence that the robust links between the social environment, health, and survival found in humans also extend to non-human social animals. A number of these studies emphasize the early life origins of these effects. For example, in several social mammals, more socially engaged mothers have infants with higher rates of survival compared to less socially engaged mothers, suggesting that positive maternal social relationships causally improve offspring survival.

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.

Environmental, sex-specific and genetic determinants of infant social behaviour in a wild primate.

Affiliative social bonds are linked to fitness components in many social mammals. However, despite their importance, little is known about how the tendency to form social bonds develops in young animals, or if the timing of development is heritable and thus can evolve. Using four decades of longitudinal observational data from a wild baboon population, we assessed the environmental determinants of an important social developmental milestone in baboons-the age at which a young animal first grooms a conspecific-and we assessed how the rates at which offspring groom their mothers develops during the juvenile period.

A Causal Mediation Model for Longitudinal Mediators and Survival Outcomes with an Application to Animal Behavior.

In animal behavior studies, a common goal is to investigate the causal pathways between an exposure and outcome, and a mediator that lies in between. Causal mediation analysis provides a principled approach for such studies. Although many applications involve longitudinal data, the existing causal mediation models are not directly applicable to settings where the mediators are measured on irregular time grids.

Social and early life determinants of survival from cradle to grave: A case study in wild baboons.

Field studies of natural mammal populations present powerful opportunities to investigate the determinants of health and aging using fine-grained observations of known individuals across the life course. Here, we synthesize five decades of findings from one such study: the wild baboons of the Amboseli ecosystem in Kenya. First, we discuss the profound associations between early life adversity, adult social conditions, and key aging outcomes in this population, especially survival.

Early life adversity and adult social relationships have independent effects on survival in a wild primate.

Adverse conditions in early life can have negative consequences for adult health and survival in humans and other animals. What variables mediate the relationship between early adversity and adult survival? Adult social environments represent one candidate: Early life adversity is linked to social adversity in adulthood, and social adversity in adulthood predicts survival outcomes. However, no study has prospectively linked early life adversity, adult social behavior, and adult survival to measure the extent to which adult social behavior mediates this relationship.

Can You Trust Who You See? The Evolution of Socially Cued Anticipatory Plasticity.

AbstractThe social environment can affect development and fitness. However, we do not know how selection acts on individuals that cue developmental pathways using features of the social environment. Socially cued anticipatory plasticity (SCAP) is a hypothetical strategy whereby juveniles use social cues to alter development to match their adult phenotype to the social environment that they expect to encounter.

Sex differences in the plasticity of life history in response to social environment.

Predicting how social environment affects life history variation is critical to understanding if, and when, selection favors alternative life history development, especially in systems in which social interactions change over time or space. Although sexual selection theory predicts that males and females should respond differently to variation in the social environment, few studies have examined the responses of both male and female phenotypes to the same gradient of social environment. In this study, we used a livebearing fish to determine how males and females altered their life histories in response to variation in the social environment during development.

Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.

Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)--(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.

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.

Biomarkers in epilepsy-A modelling perspective.

Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking.

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy.

CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model.

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).

Summary data of potency and parameter information from semi-mechanistic PKPD modeling of prolactin release following administration of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride in rats.

We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, "A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats" (Taneja et al., 2016) [1]. All information is tabulated.

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

Introduction: Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics.

Emerging Insights for Translational Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Studies: Towards Prediction of Nose-to-Brain Transport in Humans.

To investigate the potential added value of intranasal drug administration, preclinical studies to date have typically used the area under the curve (AUC) in brain tissue or cerebrospinal fluid (CSF) compared to plasma following intranasal and intravenous administration to calculate measures of extent like drug targeting efficiencies (%DTE) and nose-to-brain transport percentages (%DTP). However, CSF does not necessarily provide direct information on the target site concentrations, while total brain concentrations are not specific to that end either as non-specific binding is not explicitly considered. Moreover, to predict nose-to-brain transport in humans, the use of descriptive analysis of preclinical data does not suffice.

Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier.

The cannabinoid (CB) receptors are the main targets of the cannabinoids, which include plant cannabinoids, endocannabinoids and synthetic cannabinoids. Over the last few years, accumulated evidence has suggested a role of the CB receptors in neuroprotection. The blood-brain barrier (BBB) is an important brain structure that is essential for neuroprotection.

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).

Glutathione PEGylated liposomes: pharmacokinetics and delivery of cargo across the blood-brain barrier in rats.

Partly due to poor blood-brain barrier drug penetration the treatment options for many brain diseases are limited. To safely enhance drug delivery to the brain, glutathione PEGylated liposomes (G-Technology®) were developed. In this study, in rats, we compared the pharmacokinetics and organ distribution of GSH-PEG liposomes using an autoquenched fluorescent tracer after intraperitoneal administration and intravenous administration.

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.

[11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness.

Introduction: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar.

Methods: Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders".