Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure.

Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery. Oral absorption of pexidartinib is affected by food; administration with a high-fat meal (HFM) or low-fat meal (LFM) increases absorption by approximately 100% and approximately 60%, respectively, compared with the fasted state. Pexidartinib is currently dosed 250 mg orally twice daily with an LFM (approximately 11-14 g of total fat).

PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5'-Diphospho-glucuronosyltransferase Substrates.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed.

Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study.

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage.

Sodium-23 magnetic resonance imaging has potential for improving penumbra detection but not for estimating stroke onset time.

Tissue sodium concentration increases in irreversibly damaged (core) tissue following ischemic stroke and can potentially help to differentiate the core from the adjacent hypoperfused but viable penumbra. To test this, multinuclear hydrogen-1/sodium-23 magnetic resonance imaging (MRI) was used to measure the changing sodium signal and hydrogen-apparent diffusion coefficient (ADC) in the ischemic core and penumbra after rat middle cerebral artery occlusion (MCAO). Penumbra and core were defined from perfusion imaging and histologically defined irreversibly damaged tissue.

Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy.

Weak base therapeutic agents can show reduced absorption or large pharmacokinetic variability when coadministered with pH-modifying agents, or in achlorhydria disease states, due to reduced dissolution rate and/or solubility at high gastric pH. This is often referred to as pH-effect. The goal of this study was to understand why some drugs exhibit a stronger pH-effect than others.

In ovo non-invasive quantification of the myocardial function and mass of chick embryos using magnetic resonance imaging.

Magnetic resonance imaging (MRI) has evolved as one of the major non-invasive tools to study healthy and diseased hearts in animal models, especially rodent models. Even though, the chick embryo has long been used as a model for cardiovascular research, MRI has not yet been used for in vivo cardiac studies. Part of the reason for this is the difficulty in monitoring the ECG and respiration of the chick embryo in the magnet for gating purposes.

Serial postmortem relaxometry in the normal rat brain and following stroke.

Purpose: To investigate MRI for noninvasive autopsy by means of measurements of serial changes in relaxation parameters of the rat brain during the postmortem interval.

Materials And Methods: Postmortem relaxometry measurements were performed before and hourly after death for 24 h on five control rats and five rats that underwent middle cerebral artery occlusion. Analyses were performed on representative regions of gray, white, and mixed gray/white matter structures.

Effects of magnesium treatment in a model of internal capsule lesion in spontaneously hypertensive rats.

Background And Purpose: The study aim was to assess the effects of magnesium sulfate (MgSO(4)) administration on white matter damage in vivo in spontaneously hypertensive rats.

Methods: The left internal capsule was lesioned by a local injection of endothelin-1 (ET-1; 200 pmol) in adult spontaneously hypertensive rats. MgSO(4) was administered (300 mg/kg SC) 30 minutes before injection of ET-1, plus 200 mg/kg every hour thereafter for 4 hours.

17beta-Estradiol treatment following permanent focal ischemia does not influence recovery of sensorimotor function.

The development of therapy to aid poststroke recovery is essential. The female hormone 17beta-estradiol has been shown to promote synaptogenesis; the purpose of this study was to attempt to harness these mechanisms to promote repair and recovery in the peri-infarct zone. Rats were ovariectomized, tested for sensorimotor function, and the middle cerebral artery permanently occluded (MCAO).