Evaluation of a physiologically-based pharmacokinetic approach for simulating the first-time-in-animal study.
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Animals↗
Biomedical subjects
Philip S Burton
Publications and source records attributed to Philip S Burton.
Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat.
The relationship of rotatable bond count (N(rot)) and polar surface area (PSA) with oral bioavailability in rats was examined for 434 Pharmacia compounds and compared with an earlier report from Veber et al. (J. Med. Chem. 2002, 45, 2615). N(rot) and PSA were calculated with QikProp or Cerius2. The resulting correlations depended on the calculation method and the therapeutic class within the data superset. These results underscore that such generalizations must be used with caution.
Administration, Oral↗
Summary workshop report: biopharmaceutics classification system--implementation challenges and extension opportunities.
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Biopharmaceutics↗
Automated analysis of polyethylene glycol-induced inhibition of P-glycoprotein activity in vitro.
Previous studies in our laboratories have shown that commonly used polyethoxylated pharmaceutical excipients inhibit P-glycoprotein activity in cell culture models of the intestinal mucosa. The results presented in this technical note show that the TECAN Genesis robotic workstation can be utilized to automate cellular transport studies for evaluating excipient effects on P-glycoprotein activity in vitro and for estimating the permeation of drug-like molecules across cell monolayers.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Predicting oral absorption of drugs: a case study with a novel class of antimicrobial agents.
PURPOSE: The purpose of this work was to evaluate an oral absorption prediction model, maximum absorbable dose (MAD), which predicts a theoretical dose of drug that could be absorbed across rat intestine based on consideration of intestinal permeability, solute solubility, intestinal volume, and residence time. METHODS: In the present study, Caco-2 cell permeability, as a surrogate for rat intestinal permeability, and aqueous solubility were measured for 27 oxazolidinones. The oxazolidinones are a novel class of potential antibacterial agents currently under investigation. These values were used to estimate MAD for each of the compounds. Finally, these predicted values were compared to previously measured bioavailability data in the rat in order to estimate oral absorption properties. RESULTS: A reasonably good correlation between predicted dose absorbed and bioavailability was observed for most of the compounds. In a few cases involving relatively insoluble compounds, absorption was underestimated. For these compounds while aqueous solubility was low. solubility in 5% polysorbate 80 was significantly higher, a solvent possibly more representative of the small intestinal lumen. CONCLUSIONS: These results suggest that MAD may be useful for prioritizing early discovery candidates with respect to oral absorption potential. In the case of compounds with poor aqueous solubility, additional factors may have to be considered such as solubility in the intestinal lumen.
Administration, Oral↗
A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P-glycoprotein activity in vitro.
P-glycoprotein (P-gp), a multidrug resistance (MDR) protein encoded by the MDR1 gene in humans, is responsible for the efflux of structurally diverse drugs. Previous studies in our laboratory have shown that excipients such as poly(ethylene)glycol (PEG)-300, Cremophor EL, and Tween 80 inhibit P-gp activity in Caco-2 cell monolayers. The objective of this study was to determine the effects of these excipients in an MDR1- transfected Madin Darby Canine Kidney (MDR1-MDCK) cell line and to compare the results with those obtained from Caco-2 cells. The results presented herein show that PEG-300 (20%, v/v) causes almost complete inhibition of P-gp activity in both Caco-2 and MDR1-MDCK cell monolayers, whereas Cremophor EL (0.1%, w/v) and Tween 80 (0.05%, w/v) only partially inhibit P-gp activity in Caco-2 cells. Cremophor EL (0.1%, w/v) and Tween 80 (0.05%, w/v) were inactive as P-gp inhibitors in MDR1-MDCK cell monolayers. This inability of Tween 80 and Cremphor EL to inhibit P-gp activity in MDR1-MDCK cells may be related to differences in the interactions of the surfactants with these different cell membranes. PEG-induced changes in P-gp activity are probably related to changes in the fluidity of the polar head group regions of cell membranes.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Predicting drug absorption: how nature made it a difficult problem.
Significant recent work has focused on predicting drug absorption from structure. Several misperceptions regarding the nature of absorption seem to be common. Among these is that intestinal absorption, permeability, fraction absorbed, and, in some cases, even bioavailability, are equivalent properties and can be used interchangeably. A second common misperception is that absorption, permeability, etc. are discrete, fundamental properties of the molecule and can be predicted solely from some structural representation of the drug. In reality, drug absorption is a complex process dependent upon drug properties such as solubility and permeability, formulation factors, and physiological variables, including regional permeability differences, pH, lumenal and mucosal enzymology, and intestinal motility, among others. This article will explore the influence of these different variables on drug absorption and the implications with regards to attempting to develop predictive drug absorption algorithms.
Administration, Oral↗