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.
TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and Pgp with IC 50 values of 8.4, 12 and 7.13 lM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).Phosphodiesterase 10A (PDE10A) acts as an important regulator of signal transduction by degrading the second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate [1,2]. PDE10A is preferentially expressed in the medium spiny neurons of the striatum, a region of critical importance for domains that are disrupted in patients with schizophrenia [3][4][5].Current treatments often do not adequately address the multifaceted clinical symptomatology of schizophrenia [6]. In addition, antipsychotics are associated with cardiometabolic disturbances and cardiovascular morbidity that worsen longterm outcomes [7]. Because of the shortcomings in current treatment options for schizophrenia, PDE10A inhibition by TAK-063 is being evaluated as a new therapeutic strategy.TAK-063 is a potent and highly selective PDE10A inhibitor [8,9]. Furthermore, TAK-063 has demonstrated pre-clinical efficacy in animal models of schizophrenia. TAK-063 produced dose-dependent antipsychotic-like effects in rodent models of induced psychosis [10]. In rodents, PDE10A inhibition by TAK-063 also improved cognitive functions impaired in schizophrenia [11]. TAK-063 exhibits a favourable safety profile in a rodent study [12]. To understand the mechanism of these efficacy and safety profiles of TAK-063, the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 were investigated.In general, ADME properties using radiolabelled materials in animals and human beings are required for inclusion in the New Drug Application for new molecular entities. This report he...
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