Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data.
Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize these approaches, we proposed methods for unbound intrinsic clearance in virtually 100% humanized-liver mouse by incorporating unbound plasma fractions of compounds in differently humanized-liver mice. Comparisons of prediction accuracies of values for human clearance of 15 model compounds were performed among our current physiological and previously reported models and single-species allometry using humanized-liver mice. Incorporation of the actual unbound plasma fractions of compounds and correction of residual mice hepatocyte in humanized-liver mice showed comparable prediction accuracy to that by single-species allometry. After exclusion of 3 compounds with large species differences in values of clearance and unbound plasma fractions between mice and humans out of 15 compounds, prediction accuracies were improved in the methods investigated. The previously and present reported physiological methods could show the good prediction accuracy of values for clearance of drugs from plasma.
['Nakayama|Keigo|K|', 'Kamimura|Hidetaka|H|', 'Suemizu|Hiroshi|H|', 'Yoneda|Nao|N|', 'Nishiwaki|Megumi|M|', 'Iwamoto|Kazuhiko|K|', 'Mizunaga|Mari|M|', 'Negoro|Tamotsu|T|', 'Ito|Soichiro|S|', 'Yamazaki|Hiroshi|H|', 'Nomura|Yukihiro|Y|']
D000081:Acetamides D000420:Albuterol D000818:Animals D002219:Carbamates D002853:Chromatography, Liquid D003975:Diazepam D004008:Diclofenac D004074:Digitoxin D006801:Humans D017964:Itraconazole D007660:Ketoprofen D008099:Liver D008657:Metabolic Clearance Rate D051379:Mice D008822:Mice, Transgenic D009288:Naproxen D004364:Pharmaceutical Preparations D010672:Phenytoin D010880:Piperidines D017035:Pravastatin D011743:Pyrimidines D011802:Quinidine D053719:Tandem Mass Spectrometry D000077333:Telmisartan D016593:Terfenadine D014700:Verapamil
Single-species allometry Physiological methods Chimeric mice with humanized liver Unbound fraction