Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver

Abstract

PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [ 14 C]desloratadine, [ 3 H]mianserin, cyproheptadine, and [ 3 H]carbazeran, all reported with disproportionate human metabolites were orally administered to PXB-or control SCID mice to elucidate the biotransformation of each of them. For [ 14 C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its Oglucuronide were detected as major drug-related materials in the bile while only 3hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3hydroxydesloratadine in feces derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human ADME study where the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study, where 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared to rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at high level in PXB-mice but they were either not or minimally observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand biliary clearance mechanism of a drug.

Physiologically Based Pharmacokinetic Modeling for Quantitative Prediction of Exposure to a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Substrate of Cytochrome P450 and Aldehyde Oxidase, Using Chimeric Mice With Humanized Liver

“…indicated the dominant contribution of CYP2C8 to DS-1971a metabolism in these mice. Given the additional fact that 3-hydroxydesloratadine-glucronide, which is another human disproportionate metabolite produced sequentially by UGT2B10, CYP2C8 and then UGTs (Kazumi et al, 2015), was also detected as the predominant metabolite in the plasma of PXBmice after oral administration of desloratadine (Kato et al, 2020), PXB-mice can provide reliable qualitative information for CYP2C8-mediated formation of human disproportionate metabolites of mixed non-P450 and P450 substrates.…”

“…More than 70% of liver cells in PXB-mice are replaced with human hepatocytes and various kinds of human metabolizing enzymes and transporters are expressed in the liver of PXB-mice (Okumura et al, 2007;Hasegawa et al, 2012;Tateno et al, 2013). PXB-mice can be used for estimating human PK parameters by the allometric scaling method (Sanoh et al, 2015) and in vivo metabolite profiles in PXB-mice qualitatively reflect those in humans (Kato et al, 2020). Additionally, urinary and biliary excretion of metabolites in PXB-mice reflects that in humans (Sanoh et al, 2012;Kato et al, 2020).…”

“…PXB-mice can be used for estimating human PK parameters by the allometric scaling method (Sanoh et al, 2015) and in vivo metabolite profiles in PXB-mice qualitatively reflect those in humans (Kato et al, 2020). Additionally, urinary and biliary excretion of metabolites in PXB-mice reflects that in humans (Sanoh et al, 2012;Kato et al, 2020).…”