Mechanistic insights on clearance and inhibition discordance between liver microsomes and hepatocytes when clearance in liver microsomes is higher than in hepatocytes

Predictive In Vitro-In Vivo Extrapolation for Time Dependent Inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 Using Pooled Human Hepatocytes, Human Liver Microsomes, and a Simple Mechanistic Static Model

“…A recent publication highlighted the critical role of passive permeability to differences between clearance and inhibition parameters derived from HHEP and HLM (Keefer et al, 2020). To understand whether the time dependency observed in hepatocytes may be an artifact of low/slow permeability followed by direct inhibition, reported information on the biopharmaceutics classification system (BCS) and direct inhibition parameters was collected (Supplemental Table 8).…”

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

“…The hepatocyte relay method has been applied not only to measuring intrinsic clearance, but also for metabolite identification and reaction phenotyping 21 , 51 . The characteristics of the method is summarized in Table 2 52 , 53 , 54 , 55 , 56 , 57 , 58 .…”

“…Maximum measurable t 1/2 ( t 1/2,max ) is twice incubation time 58 . b CL int, app, scaled = CL int, app × 21 × 120/1000 (mL/min/kg) 57 . …”

“… a CL int, app = ln2/( t 1/2, max )/cell density × 1000 (μL/min/million cells) 57 . Maximum measurable t 1/2 ( t 1/2,max ) is twice incubation time 58 .…”

Permeabilized Cryopreserved Human Hepatocytes as an Exogenous Metabolic System in a Novel Metabolism-Dependent Cytotoxicity Assay for the Evaluation of Metabolic Activation and Detoxification of Drugs Associated with Drug-Induced Liver Injuries: Results with Acetaminophen, Amiodarone, Cyclophosphamide, Ketoconazole, Nefazodone, and Troglitazone

“…2. Due to permeabilization, plasma membranes no longer serve as a barrier for drug entry and metabolite exit, thereby allowing the evaluation of the metabolic fate of drugs with low permeability (Keefer et al, 2020). 3.…”