Comparison of in vitro hepatic models for the prediction of metabolic interaction between simvastatin and naringenin.
The study of potential interaction at a very early stage of drug development requires suitable in vitro models that describe drug interactions both qualitatively and quantitatively. The purpose of this work was to help assessing the predictive value of in vitro drug interaction test with liver microsomal fractions and hepatocytes by determination of enzymatic parameters such as the inhibition constant (Ki) and the intrinsic clearance (Clint). This study was conducted to compare different methods of Ki calculation and to determine the most suitable parameter for describing drug interactions. The metabolic interaction between SV and NRG was used as a model to help verifying the suitability of the in vitro model for predicting the kind and degree of metabolic drug interactions. The method of Ki calculation using linearized versions of Michaelis Menten equations based on the simultaneous non linear regressions and the "km app" approach accurately estimated the Ki values. The linear representation of an inherently non linear relationship was only used to establish the mechanism of inhibition and the Clint could be used to predict drug interactions. To further prediction in humans, it seems likely that the simultaneous application of both systems, microsomal fractions and hepatocytes will yield conclusions.
Le Goff
N
N
Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France.
Koffel
J C
JC
Vandenschrieck
S
S
Jung
L
L
Ubeaud
G
G
D000818:Animals; D002853:Chromatography, Liquid; D004347:Drug Interactions; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D044950:Flavanones; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D011237:Predictive Value of Tests; D051381:Rats; D019821:Simvastatin / Q000378:metabolism / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
D004965:Estrogen Antagonists; D044950:Flavanones; D005419:Flavonoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C005273:naringenin