RT Journal Article
SR Electronic
T1 An investigation into the prediction of in vivo clearance for a range of Flavin-containing monooxygenase substrates
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.077396
DO 10.1124/dmd.117.077396
A1 Barry C Jones
A1 Abhishek Srivastava
A1 Nicola Colclough
A1 Joanne Wilson
A1 Venkatesh Pilla Reddy
A1 Sara Amberntsson
A1 Danxi Li
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/08/07/dmd.117.077396.abstract
AB Flavin-containing monooxygenases (FMO) are metabolic enzymes mediating the oxidation of nucleophilic atoms such as nitrogen, sulfur, phosphorus and selenium. The enzymes share similar properties to the cytochrome P450 system but can be differentiated through lability to heat and selective inhibition by methimazole. This study investigated 10 compounds with varying degrees of FMO involvement to determine the nature of the correlation between human in-vitro and in-vivo unbound intrinsic clearance. In order to confirm and quantify the extent of FMO involvement 6 of the compounds were investigated in human liver microsomal (HLM) in-vitro assays with heat deactivation and methimazole inhibition. Under these conditions FMO contribution varied from 21% (imipramine) to 96% (itopride). Human hepatocyte and HLM intrinsic clearance (Clint) data was scaled using standard methods to determine the predicted unbound intrinsic clearance (predicted Clint u) for each compound. This was compared with observed unbound intrinsic clearance (observed Clint u) values back calculated from human pharmacokinetic studies. A good correlation was observed between the predicted and observed Clint u using hepatocytes with 8 out of the 10 compounds investigated within or close to a factor of 2-. For HLM the in vitro-in vivo correlation was maintained but the accuracy was reduced with only 3 out of 10 compounds falling within or close to 2-fold. This study demonstrates that human hepatocytes and human liver microsomes can be used with standard scaling approaches to predict the human in vivo clearance for FMO substrates.