Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates with Estron e-3-Sulfate Transport in Caco-2

Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression … Continued

Modeling of Pharmacokinetic Systems Using Stochastic Deconvolution

In environments where complete mechanistic knowledge of the system dynamics is not available, a synergy of first-principle concepts, stochastic methods and statistical approaches can provide an efficient, accurate, and insightful strategy for model development. In this work, a system of ordinary differential equations describing system pharmacokinetics (PK) was coupled to a Wiener process for tracking the … Continued

Application of Permeability-limited Physiologically-based Pharmacokinetic Models: Part I—Digoxin Pharmacokinetic Incorporating P-glycoprotein-mediated Efflux

A prerequisite for the prediction of the magnitude of P-glycoprotein (P-gp)-mediated drug-drug interactions between digoxin and P-gp inhibitors (e.g. verapamil and its metabolite norverapamil) or P-gp inducers (e.g. rifampicin) is a predictive pharmacokinetic model for digoxin itself. Thus, relevant in vitro metabolic, transporter and inhibitory data incorporated into permeability-limited models, such as the “advanced dissolution, … Continued

Application of Permeability-limited Physiologically-based Pharmacokinetic Models: Part II—Prediction of P-glycoprotein Mediated Drug-drug Interactions with Digoxin

Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite … Continued

Prediction of Concentration-time Profile and Its Inter-individual Variability Following the Dermal Drug Absorption

Estimation of systemic exposure after absorption of any xenobiotic from the skin is very important in development of dermal pharmaceutical products as well as assessing un-intended exposures due to cosmetic products or environmental and occupational compounds. Historically, animal models have been used to evaluate dermal drug absorption before conducting human trials. However, occasional disparity between … Continued

Noninvasive Real-time Fluorescence Imaging of the Lymphatic Uptake of BSA-IRDye 680 Conjugate Administered Subcutaneously in Mice

The goal of our studies was to determine lymphatic uptake of bovine serum albumin (BSA) using real-time noninvasive fluorescence imaging. BSA labeled with near-infrared dye (IRDye) 680 was used as a model protein-dye conjugate. The conjugation of BSA with IRDye 680 was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Size-exclusion high-performance liquid chromatography and … Continued

Influence of Route of Administration and Liposomal Encapsulation on Blood and Lymph Node Exposure to the Protein VEGF-C156S

VEGF-C156S is a recombinant form of human vascular endothelial growth factor C (VEGF-C), which targets the receptor VEGFR-3 present in the lymphatics. VEGF-C156S has lymphangiogenic properties and may represent a potential therapeutic approach in treating the lymphatic disease lymphedema. In the present study, we tested the hypotheses that (1) subcutaneous (s.c.) injection will provide higher … Continued

Metabolism of Dextrorphan by CYP2D6 in Different Recombinantly Expressed Systems and Its Implications for the In Vitro Assessment of Dextromethorphan Metabolism

Cytochrome P450 2D6 (CYP2D6) mediated formation of dextrorphan (DOR) from dextromethorphan (DEX) is widely used as a marker to assess the activity of this enzyme both in vitro and in vivo. The sequential metabolism of DOR during in vitro studies, particularly using recombinant systems (rCYPs) expressing human CYP2D6, is assumed to be negligible. The extent … Continued

Prediction of Plasma Protein Binding Displacement and Its Implications for Quantitative Assessment of Metabolic Drug-drug Interactions from In Vitro Data

Although displacement from plasma protein binding (dPB) is usually of little clinical significance, it should be taken into account when interpreting changes in total plasma concentrations of drugs subject to metabolically based drug-drug interactions (mDDI). The aim of this study was to develop an approach to predict changes in the free fractions (fu) of pairs … Continued

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