Pharmacological research : the official journal of the Italian Pharmacological Society
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Brigatinib is an FDA-approved oral anaplastic lymphoma kinase (ALK) inhibitor for treatment of metastatic non-small cell lung cancer (NSCLC). Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3 A in plasma pharmacokinetics and tissue distribution of brigatinib. In vitro, brigatinib was exceptionally well transported by human ABCB1 and mouse Abcg2, and efficiently by human ABCG2. ⋯ ABCB1 and ABCG2 thus limit brain accumulation, toxicity, and systemic exposure of brigatinib, whereas CYP3 A also markedly restricts its oral availability. Unexpected toxicities should therefore be carefully monitored when brigatinib is coadministered with ABCB1/ABCG2 inhibitors in patients. Collectively, these insights may support the clinical application of brigatinib.
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Risperidone, one of the second-generation antipsychotics, can efficiently target dopamine D2 and serotonin 5-HT2A receptors. There actually exists significant implication of CYP2D6 genetic polymorphisms on the metabolic kinetics of risperidone, little is known about the extent of CYP2D6 impacting human D2 and 5-HT2A receptor occupancies as well as the clinical efficacy and efficacy in schizophrenia treatment. Here we assessed the influences of CYP2D6 gene polymorphisms on human target occupancies/clinical outcomes and optimized the maintenance therapy of risperidone. ⋯ The predictions of human D2, 5-HT2A RO, PANSS and SAS changes for risperidone with CYP2D6 genetic polymorphisms were well in line with the reported values in clinic. 5.0, 4.0 and 2.5 mg/day were the equivalent dosages of risperidone for CYP2D6 PM, IM and EM, respectively. The optimized maintenance therapy of risperidone was provided through the Three-Step method and the dosage range was 2.5-5.0 mg/day for three CYP2D6 gene groups in the present study. Taken together, our findings demonstrate that this extended translational framework not only differentiates the effects of CYP2D6 genetic polymorphisms on target occupancies and clinical outcomes, but also constitutes a scientific basis to optimize the maintenance therapy of neuropsychiatric patients in clinic.