title: Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human.
abstract: Integral to the discovery of new pharmaceutical entities is the ability to predict in vivo pharmacokinetic parameters from early stage in vitro data generated prior to the onset of clinical testing. Within the pharmaceutical industry, a whole host of assay methods and mathematical models exist to predict the in vivo pharmacokinetic parameters of drug candidates. One of the most important pharmacokinetic properties of new drug candidates predicted from these methods and models is the hepatic clearance. Current methods, while useful, are still limited in their predictive efficacy. In order to address this issue, we have established a novel microfluidic in vitro culture system, the patented HmuREL device. The device comprises multiple compartments that are designed to be proportional to the physiological architectures and enhanced with the consideration of flow. Here we demonstrate the functionality of the liver-relevant chamber in the HmuREL device, and the feasibility of utilizing our system for predicting hepatic clearance. Cryopreserved human hepatocytes from a single donor were seeded within the HmuREL device to predict the in vivo hepatic clearance (CL(H)) of six marketed model compounds (carbamazepine, caffeine, timolol, sildenafil, imipramine, and buspirone). The intrinsic clearance rates from static culture controls, as well as clearance rates from the HmuREL device were subsequently compared to in vivo data available from the literature.
authors.affiliation: Hurel Corporation, Beverley Hills, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chao
authors.forename: T
authors.initials: T
authors.lastname: Maguire
authors.forename: E
authors.initials: E
authors.lastname: Novik
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
authors.forename: M L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology; D008657:Metabolic Clearance Rate; D044085:Microfluidics / Q000379:methods*; D008862:Microsomes, Liver / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations