Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Drug Metab Dispos ; 42(3): 459-68, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24396143

ABSTRACT

Well-established techniques are available to predict in vivo hepatic uptake and metabolism from in vitro data, but predictive models for biliary clearance remain elusive. Several studies have verified the expression and activity of ATP-binding cassette (ABC) efflux transporters central to biliary clearance in freshly isolated rat hepatocytes, raising the possibility of predicting biliary clearance from in vitro efflux measurements. In the present study, short-term plated rat hepatocytes were evaluated as a model to predict biliary clearance from in vitro efflux measurements before major changes in transporter expression known to take place in long-term hepatocyte cultures. The short-term cultures were carefully characterized for their uptake and metabolic properties using a set of model compounds. In vitro efflux was studied using digoxin, fexofenadine, napsagatran, and rosuvastatin, representing compounds with over 100-fold differences in efflux rates in vitro and 60-fold difference in measured in vivo biliary clearance. The predicted biliary clearances from short-term plated rat hepatocytes were within 2-fold of measured in vivo values. As in vitro efflux includes both basolateral and canalicular effluxes, pronounced basolateral efflux may introduce errors in predictions for some compounds. In addition, in vitro rat hepatocyte uptake rates corrected for simultaneous efflux predicted rat in vivo hepatic clearance of the biliary cleared compounds with less than 2-fold error. Short-term plated hepatocytes could thus be used to quantify hepatocyte uptake, metabolism, and efflux of compounds and considerably improve the prediction of hepatic clearance, especially for compounds with a large biliary clearance component.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Bile/metabolism , Hepatocytes/metabolism , Models, Biological , Pharmaceutical Preparations/metabolism , Animals , Blood Proteins/metabolism , Cells, Cultured , Chromatography, Liquid , Cytochrome P-450 Enzyme System/metabolism , Hepatocytes/drug effects , Hepatocytes/enzymology , Male , Metabolic Clearance Rate , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Predictive Value of Tests , Protein Binding , Rats , Rats, Sprague-Dawley , Substrate Specificity , Tandem Mass Spectrometry , Time Factors
2.
Pharm Res ; 28(7): 1561-76, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21347567

ABSTRACT

PURPOSE: To quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of PGE(2) and TXB(2). METHODS: Analgesia was investigated in a rat model with carrageenan-induced arthritis using a gait analysis method. Antipyretics were studied in a yeast-induced fever model using telemetrically recorded body temperature. Inhibition of TXB(2) and PGE(2) synthesis was determined ex vivo. Pharmacokinetic profiles were obtained in satellite animals. Population PKPD modeling was used to analyze the data. RESULTS: The IC(50) values (95% CI) of naproxen for analgesia (27 (0-130) µM), antipyretics (40 (30-65) µM) and inhibition of PGE(2) (13 (6-45) µM) were in similar range, whereas inhibition of TXB(2) (5 (4-8) µM) was observed at lower concentrations. Variability in the behavioral measurement of analgesia was larger than for the other endpoints. The inhibition of fever by naproxen was followed by an increased rebound body temperature. CONCLUSION: Due to better sensitivity and similar drug-induced inhibition, the biomarker PGE(2) and the antipyretic effect would be suitable alternative endpoints to the analgesic effects for characterization and comparisons of potency and time-courses of drug candidates affecting the COX-2 pathway and to support human dose projections.


Subject(s)
Dinoprostone/metabolism , Gene Expression Regulation/drug effects , Models, Chemical , Naproxen/pharmacology , Naproxen/pharmacokinetics , T-Box Domain Proteins/metabolism , Animals , Antipyretics/pharmacokinetics , Antipyretics/pharmacology , Arthritis/drug therapy , Arthritis/metabolism , Disease Models, Animal , Fever/drug therapy , Fever/metabolism , Inhibitory Concentration 50 , Male , Oxytocics/antagonists & inhibitors , Oxytocics/pharmacokinetics , Oxytocics/pharmacology , Pain/drug therapy , Pain/metabolism , Rats , Rats, Sprague-Dawley , Time Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...