title: Extrahepatic metabolism may complicate the IVIVC in rats.
abstract: As the liver is generally considered the organ most involved in metabolic transformations, metabolism in other organs is often overlooked and in vitro screening systems largely adopted in drug discovery are generally based on liver tissue fractions. First pharmacokinetics of new chemical entities (NCEs) are initially based on preclinical species; rat is used in the majority of the cases to assess early in vitro-in vivo correlation (IVIVC). It is important, in this perspective, to address as early as possible the relevant differences between rat and human and the limits using pharmacokinetic studies in this species as a model for the human PK. In this paper the author reports at least three clear examples in drug discovery where the use of hepatic in-vitro systems resulted in a very poor IVIVC due to relevant extrahepatic metabolism in rats.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetic, CiToxLAB France, 27005 Evreux, France. massimiliano.fonsi@gmail.com.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fonsi
mesh_terms: D000818:Animals; D001711:Biotransformation; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D018683:Excitatory Amino Acid Agents / Q000493:pharmacokinetics*; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D013045:Species Specificity
chemical_list: D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D056572:Histone Deacetylase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018094:Receptors, Metabotropic Glutamate; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; C108823:metabotropic glutamate receptor 4