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. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug-drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro-in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.

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. To overcome this complication, this paper presents the use of retrospective Cine MRI to measure the cardiac function of chick embryos in ovo for the first time, without the need for respiratory or cardiac gating. The resulting left ventricular functional parameters, from six chick embryos at 20 days of incubation, were (mean +/- SD) EDV 69 +/- 15 microL, ESV 31 +/- 7 microL, SV 38 +/- 9 microL and EF 54.5 +/- 2%. The use of retrospective Cine MRI at earlier stages of development is also discussed and difficulties have been highlighted.

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. RESULTS: Significant decreases in both T(1) and T(2) values were measured in all areas in the control group within 24 h of death. In the stroke animals, T(2) differences between normal and ischemic striatal tissue decreased by 11 +/- 4% (P < 0.01), with a complete convergence of T(2) values observed between ischemic striatal tissue and nonischemic cortical tissue. CONCLUSION: Lesion conspicuity and the ability to differentiate between different tissue compartments are significantly affected by postmortem interval, and alterations to pulse timing parameters will be necessary if the sensitivity of MRI to detect central nervous system diseases in postmortem tissue is to be maintained. Indeed in the case of stroke at least, convergence of T(2) values with normal tissue post mortem indicates that T(1)-weighted images may be more sensitive to the presence of such lesions.