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Yadav J , Korzekwa K , Nagar S
Impact of Lipid Partitioning on the Design, Analysis, and Interpretation of Microsomal Time-Dependent Inactivation
Drug Metab Dispos. 2019 Jul;47(7) :732-742
PMID: 31043439 PMCID: PMC6556519 URL: https://www.ncbi.nlm.nih.gov/pubmed/31043439
AbstractNonspecific drug partitioning into microsomal membranes must be considered for in vitro-in vivo correlations. This work evaluated the effect of including lipid partitioning in the analysis of complex TDI kinetics with numerical methods. The covariance between lipid partitioning and multiple inhibitor binding was evaluated. Simulations were performed to test the impact of lipid partitioning on the interpretation of TDI kinetics, and experimental TDI datasets for paroxetine (PAR) and itraconazole (ITZ) were modeled. For most kinetic schemes, modeling lipid partitioning results in statistically better fits. For MM-IL simulations (KI,u = 0.1 microM, kinact = 0.1 minute(-1)), concurrent modeling of lipid partitioning for an fumic range (0.01, 0.1, and 0.5) resulted in better fits compared with post hoc correction (AICc: -526 vs. -496, -579 vs. -499, and -636 vs. -579, respectively). Similar results were obtained with EII-IL. Lipid partitioning may be misinterpreted as double binding, leading to incorrect parameter estimates. For the MM-IL datasets, when fumic = 0.02, MM-IL, and EII model fits were indistinguishable (deltaAICc = 3). For less partitioned datasets (fumic = 0.1 or 0.5), the inclusion of partitioning resulted in better models. The inclusion of lipid partitioning can lead to markedly different estimates of KI,u and kinact A reasonable alternate experimental design is nondilution TDI assays, with post hoc fumic incorporation. The best fit models for PAR (MIC-M-IL) and ITZ (MIC-EII-M-IL and MIC-EII-M-Seq-IL) were consistent with their reported mechanism and kinetics. Overall, experimental fumic values should be concurrently incorporated into TDI models with complex kinetics, when dilution protocols are used.
Notes1521-009x Yadav, Jaydeep Korzekwa, Ken Nagar, Swati R01 GM104178/GM/NIGMS NIH HHS/United States R01 GM114369/GM/NIGMS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural United States Drug Metab Dispos. 2019 Jul;47(7):732-742. doi: 10.1124/dmd.118.085969. Epub 2019 May 1.