Examination of the Utility of the High Throughput In Vitro Metabolic Stability Assay to Estimate In Vivo Clearance in the Mouse
S Sarawek*, 1, L Li1, X.Q Yu1, S Rooney1, A Nouraldeen1, L Moran1, L.A Rodriguez2, J Zhang3, A.G.E Wilson1
1 Drug Metabolism, Pharmacokinetics and Toxicology, Lexicon Pharmaceutical Inc., the Woodlands, Texas, USA
2 Enterprise informatics, Lexicon Pharmaceutical Inc., the Woodlands, Texas, USA
3 Keystone Analytical, Inc, a PharmaNet Company, 401A Industrial Drive, North Wales, PA, 19454, USA
In vitro determination of metabolic stability is routinely used to assess the overall metabolic liability of compounds and for prioritization for in vivo studies. If in vitro metabolic stability data could be used to reliably predict in vivo clearance (CL), it would add significant value in the selection of compounds for in vivo pharmacokinetic and pharmacology studies. We have evaluated the utility of our in vitro metabolic stability screening assay to estimate in vivo CL in the mouse. The in vitro mouse clearances (CLin vitro) of 146 structurally diverse compounds with metabolic stabilities > 30 %, were compared to mouse in vivo CL data. Approximately 45 % of the compounds showed agreement between in vivo CL and predicted CLin vitro within a 2-fold error criteria. The correlation appeared worse when correction for the extent of incorporation of plasma protein binding or both plasma and S9 bindings (i.e. ~14 % and~ 28 % agreement, respectively). Classification of the compounds into three groups based on in vivo CL (<30 mL/min/kg, 30-70 mL/min/kg, and >70 mL/min/kg) did not show any improvement between in vivo CL and predicted CLin vitro. The percentage of compounds falling within the 2-fold error criteria for low CL, moderate CL and high CL groups were 54, 31 and 24 %, respectively. In conclusion, our analysis suggests that in vitro metabolic stability data, as routinely obtained in early ADME screening protocols, does not demonstrate a strong correlation with or predictivity for, absolute in vivo CL in the mouse.
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* Address correspondence to this author at the Drug Metabolism, Pharmacokinetics, Toxicology and Pathology, Lexicon Pharmaceutical Inc., The Woodlands, Texas, USA; Tel: (281) 863 3267; E-mail:firstname.lastname@example.org