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1.
Toxicol Lett ; 343: 34-43, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33639197

RESUMO

The present study aimed at incorporating active renal excretion via the organic cation transporter 2 (OCT2) into a generic rat physiologically based kinetic (PBK) model using an in vitro human renal proximal tubular epithelial cell line (SA7K) and mepiquat chloride (MQ) as the model compound. The Vmax (10.5 pmol/min/mg protein) and Km (20.6 µM) of OCT2 transport of MQ were determined by concentration-dependent uptake in SA7K cells using doxepin as inhibitor. PBK model predictions incorporating these values in the PBK model were 6.7-8.4-fold different from the reported in vivo data on the blood concentration of MQ in rat. Applying an overall scaling factor that also corrects for potential differences in OCT2 activity in the SA7K cells and in vivo kidney cortex and species differences resulted in adequate predictions for in vivo kinetics of MQ in rat (2.3-3.2-fold). The results indicate that using SA7K cells to define PBK parameters for active renal OCT2 mediated excretion with adequate scaling enables incorporation of renal excretion via the OCT2 transporter in PBK modelling to predict in vivo kinetics of mepiquat in rat. This study demonstrates a proof-of-principle on how to include active renal excretion into generic PBK models.


Assuntos
Rim/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Piperidinas/farmacocinética , Reguladores de Crescimento de Planta/farmacocinética , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Túbulos Renais Proximais/citologia , Modelos Biológicos , Transportador 2 de Cátion Orgânico/genética , Piperidinas/urina , Ratos
2.
Anal Chem ; 93(4): 2144-2151, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33470103

RESUMO

Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. One- and 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic Tmax), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.


Assuntos
Intestinos/química , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Administração Oral , Animais , Masculino , Piperidinas/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
3.
J Med Chem ; 63(24): 15864-15882, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33314938

RESUMO

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.


Assuntos
Piperidinas/química , Receptores CXCR/antagonistas & inibidores , Administração Oral , Amidas/química , Aminas/química , Animais , Quimiocina CXCL12/sangue , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Conformação Molecular , Piperidinas/metabolismo , Piperidinas/farmacocinética , Ligação Proteica , Ratos , Receptores CXCR/genética , Receptores CXCR/metabolismo , Relação Estrutura-Atividade
4.
Clin Drug Investig ; 40(7): 603-615, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399853

RESUMO

BACKGROUND AND OBJECTIVE: SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H3R) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics. METHODS: A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure. CONCLUSION: SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.


Assuntos
Morfolinas/efeitos adversos , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversos , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Agonismo Inverso de Drogas , Feminino , Voluntários Saudáveis , Histamina , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Piperidinas/farmacocinética
5.
Jpn J Clin Oncol ; 50(8): 859-866, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32328660

RESUMO

OBJECTIVES: Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506). METHODS: Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment. RESULTS: Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1-2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily. CONCLUSIONS: These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.


Assuntos
Grupo com Ancestrais do Continente Asiático , Neoplasias/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Piridazinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia
6.
J Pharmacol Exp Ther ; 374(1): 223-232, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32238455

RESUMO

1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) that have much better efficacy in relieving nociceptive response than the Food and Drug Administration-approved drug gabapentin in a rodent model of diabetic neuropathy. Experiments conducted in sEH knockout mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, in which TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity that we refer to as a refractory pool. The total amount of sEH enzyme in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants of TPPU and TCPU were predicted to be 2.24 and 2.67 hours-1, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy. SIGNIFICANCE STATEMENT: Although target-mediated drug disposition (TMDD) models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.


Assuntos
Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Modelos Biológicos , Terapia de Alvo Molecular , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/química , Compostos de Fenilureia/farmacocinética , Piperidinas/farmacocinética , Solubilidade
7.
Pharm Biol ; 58(1): 225-230, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32202190

RESUMO

Context: Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics.Objective: This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats.Materials and methods: Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 µL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS.Results: Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC0-24 of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant (p < 0.05). Compared with the control group, the Tmax was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h (p < 0.05), and the MRT(0-24) was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h (p < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg (p < 0.05) in experimental group. Although the Cmax and t1/2 of tofacitinib were increased, there were no significant differences (p > 0.05).Conclusions: This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/farmacocinética , Flavanonas/farmacologia , Piperidinas/farmacologia , Piperidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Pirróis/farmacologia , Pirróis/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Flavanonas/administração & dosagem , Piperidinas/administração & dosagem , Piperidinas/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirróis/administração & dosagem , Pirróis/sangue , Ratos Sprague-Dawley , Razão Sinal-Ruído
8.
Artigo em Inglês | MEDLINE | ID: mdl-32174544

RESUMO

Pimavanserin is a new drug approved by the FDA for Parkinson's disease psychosis and other neurological disorders such as Alzheimer's disease. In this study, we developed a UPLC-MS/MS method to quantify pimavanserin disposition in the brain and its pharmacokinetics in mice. Vilazodone was used as the internal standard. Pimavanserin and IS were extracted by liquid-liquid extraction using tert-butyl methyl ether and separated using an Acquity UPLC BEH™ C18 column. The mobile phase consisted of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in 20 mM ammonium acetate buffer) (A: B, 70:30 v/v) at a flow rate of 0.25 ml/min. The multiple reaction monitoring transitions were performed at m/z 428.23 â†’ 98.15 for pimavanserin and m/z 441.70 > 155.03 for the IS. The developed method was found to be sensitive, fast, and reproducible. The linearity of the method was ˃0.99 over the range of 0.1-300 ng/mL in plasma and 0.25-300 ng/g in the brain homogenate. Precision and accuracy were within the acceptance range. The method was applied to pharmacokinetics and brain uptake studies, which showed that pimavanserin penetrates the blood-brain barrier and reaches a Cmax of 21.9 ± 6.66 ng/g in 2.0 h. We also found that pimavanserin brain to plasma ratio (Kbrain/plasma) is 0.16 ± 0.05 and it is rapidly eliminated.


Assuntos
Piperidinas/metabolismo , Piperidinas/farmacocinética , Ureia/análogos & derivados , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Extração Líquido-Líquido , Camundongos , Plasma/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Ureia/metabolismo , Ureia/farmacocinética
9.
J Med Chem ; 63(5): 2688-2704, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31951130

RESUMO

A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Indóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores Opioides/agonistas , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Células CACO-2 , Modelos Animais de Doenças , Humanos , Indóis/química , Indóis/farmacocinética , Masculino , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
10.
Mol Imaging Biol ; 22(4): 931-939, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31907846

RESUMO

PURPOSE: [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [18F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability. PROCEDURE: Ninety-minute dynamic [18F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 µg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [18F]FEOBV scans were performed 1 week apart. RESULTS: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate Ki showed a lower coefficient of variation (COV, 14-24 %) than the volume of distribution VT (16-108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12-27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14-32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good. CONCLUSION: [18F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.


Assuntos
Encéfalo/metabolismo , Modelos Biológicos , Piperidinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor , Humanos , Cinética , Ligantes , Masculino , Piperidinas/sangue , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/sangue , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Especificidade da Espécie , Distribuição Tecidual , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
11.
Luminescence ; 35(2): 284-291, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31762136

RESUMO

The direct determination of alogliptin benzoate (ALO) using fluorescence has not yet been accomplished because ALO cannot fluoresce naturally. Accordingly, it should be derivatized first with a fluorogenic reagent to enhance the sensitivity required for its bioanalysis. This method is the first spectrofluorimetric assay for ALO quantification exploiting the nucleophilic nature of its amino group to react with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer at pH 8.5 to produce a strong fluorescent compound that is excited at and emits at wavelengths 470 and 527 nm, respectively. Experimental variables concerning the conditions of reaction and fluorogenic intensity were carefully investigated and optimized. Linearity was from 1-250 ng ml-1 with a lower detection limit of 0.29 ng ml-1 and a lower quantification limit of 0.88 ng ml-1 . Validation of the current study was accomplished with mean per cent recovery of 100.62 ± 1.59 in tablets and 99.86 ± 0.82 in human plasma. Furthermore, the current method has been utilized in the bioanalysis of ALO in real rat plasma after oral administration with a simple specimen preparation. The developed method has proven to be a promising alternative method for ALO analysis in bioequivalence studies.


Assuntos
4-Cloro-7-nitrobenzofurazano/química , Benzoatos/sangue , Corantes Fluorescentes/química , Piperidinas/sangue , Espectrometria de Fluorescência , Uracila/análogos & derivados , Animais , Benzoatos/química , Benzoatos/farmacocinética , Humanos , Masculino , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacocinética , Teoria Quântica , Ratos , Ratos Wistar , Espectrometria de Fluorescência/instrumentação , Uracila/sangue , Uracila/química , Uracila/farmacocinética
12.
Leuk Res ; 88: 106286, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865062

RESUMO

Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (NHL), is categorized into two major subtypes, activated B-cell-like (ABC) and germinal center B-cell-like (GCB). The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy. The B-cell receptor (BCR) pathway is activated in ABC DLBCL, suggesting that inhibition of this pathway could provide an alternative strategy for treatment. Naquotinib is an irreversible tyrosine kinase inhibitor (TKI) originally designed to target the epidermal growth factor receptor (EGFR). As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib. Naquotinib inhibited BTK kinase activity with similar potency to that for EGFR activating mutations. In vivo, naquotinib induced tumor regression and suppressed tumor recurrence in TMD8 and OCI-Ly10, ABC DLBCL cell line xenograft models, at a lower dose than the clinically relevant dose. Compared to other BTK inhibitors, naquotinib showed faster onset and comparable inhibition of BTK following incubation with cell lines for 3 and 20 h. In addition, naquotinib showed longer continuous inhibition of BTK following removal of the compound, lasting for at least 26 h after removal. Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients.


Assuntos
Linfócitos B/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Pirazinas/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores de Antígenos de Linfócitos B/efeitos dos fármacos , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Células Cultivadas , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Antígenos de Linfócitos B/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Drug Metab Pharmacokinet ; 45(2): 265-272, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31820304

RESUMO

BACKGROUND AND OBJECTIVE: Bilastine is a non-sedating H1 antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this trial was to assess the bioequivalence of three novel pediatric oral formulations of bilastine. METHODS: An open label, randomized, four-treatment-period, four-sequence, crossover, single-center study was conducted in 23 healthy volunteers. Each subject received four single doses of bilastine under fasting conditions: a 10-mg orodispersible tablet (DT1), a 10-mg oral solution (SOL), a 10-mg orodispersible tablet without water (DT2dry), and a 10-mg orodispersible tablet with water (DT2water, reference formulation). Blood samples were collected during 72 h with a washout period of at least 7 days. Bilastine maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between 0 to t time (AUC0-t) were calculated to assess bioequivalence. Tolerability was evaluated throughout the study. RESULTS: The three oral pediatric formulations tested were bioequivalent to the reference formulation as determined by the ratio test/reference of the geometric mean and their 90% confidence intervals (between 0.80 and 1.25) for the Cmax, AUC0-t and AUC0-∞. Bilastine was well tolerated when administered indistinctly as an orodispersible tablet or as an oral solution. CONCLUSION: The three oral pediatric formulations tested were found to be bioequivalent to the reference formulation. All formulations were well tolerated. TRIAL REGISTRATION: Spanish Clinical Studies Registry (REEC) number 2014-000786-41.


Assuntos
Benzimidazóis/administração & dosagem , Antagonistas dos Receptores Histamínicos H1 não Sedativos/administração & dosagem , Piperidinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Estudos Cross-Over , Jejum , Feminino , Antagonistas dos Receptores Histamínicos H1 não Sedativos/farmacocinética , Humanos , Masculino , Soluções Farmacêuticas , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Comprimidos , Equivalência Terapêutica , Adulto Jovem
14.
Cancer Chemother Pharmacol ; 85(2): 391-399, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31875923

RESUMO

PURPOSE: Zanubrutinib (BGB-3111) is a potent Bruton's tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects. METHODS: In this open-label, two-part clinical study, 20 participants received a single oral dose of zanubrutinib (320 mg) and oral rifampin (600 mg) in Part A, and 18 participants received a single oral dose of zanubrutinib (20 mg) and oral itraconazole (200 mg) in Part B. Serial blood samples were collected after administration of zanubrutinib alone and zanubrutinib in combination with rifampin or itraconazole for the measurement of PK parameters. RESULTS: Coadministration with rifampin decreased AUC0-∞ of zanubrutinib by 13.5-fold and Cmax by 12.6-fold. Coadministration with itraconazole increased the AUC0-∞ of zanubrutinib by 3.8-fold and Cmax by 2.6-fold. The PK of zanubrutinib was consistent between Asian and non-Asian subjects, and  zanubrutinib was well tolerated in this study. CONCLUSIONS: These results confirm that zanubrutinib is primarily metabolized by CYP3A in humans. The PK of zanubrutinib was comparable between Asian and non-Asian subjects and, therefore, no dose modifications are necessary for zanubrutinib in these ethnic populations.


Assuntos
Indutores do Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Itraconazol/uso terapêutico , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Rifampina/uso terapêutico , Adolescente , Adulto , Idoso , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121875, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790916

RESUMO

The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200 ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic studies in healthy male and female Sprague Dawley rats. The animals were dosed through oral gavage (50 mg/kg) and intravenously (2.5 mg/kg). Test samples were analyzed using the validated bioanalytical method to generate plasma concentration-time profiles. The results were further subjected to non-compartmental analysis using Phoenix 6.4®. MES207 exhibits a large volume of distribution (1.2 ±â€¯0.6 L), high clearance (0.8 ±â€¯0.1 L/h), and a poor oral bioavailability (1.7 ±â€¯0.4%). The compound also showed a multiple peak phenomenon with a very short absorption phase. It appears that gender does not significantly influence the differences in pharmacokinetic parameters of this NPFF probe.


Assuntos
Guanidinas/sangue , Guanidinas/farmacocinética , Piperidinas/sangue , Piperidinas/farmacocinética , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Feminino , Guanidinas/química , Limite de Detecção , Modelos Lineares , Masculino , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
16.
Drug Des Devel Ther ; 13: 4091-4105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819376

RESUMO

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Administração Oral , Humanos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética
17.
Artigo em Inglês | MEDLINE | ID: mdl-31704620

RESUMO

A novel, high throughput and sensitive LC-MS/MS assay method was developed and fully validated for quantitative determination of pioglitazone, its hydroxyl metabolite and alogliptin in human plasma. A simple and rapid sample preparation procedure based on protein precipitation technique with acetonitrile was utilized. Chromatographic separation was achieved on C8 (50 × 4.6 mm, 5 µm) Kinetex® analytical column using methanol and 0.1% formic acid in a gradient elution mode at a flow rate of 0.7 mL/min with injection volume of 8 µL. Detection was performed on a triple quadrupole mass spectrometer accompanied with electrospray ionization (ESI) technique in positive mode, operating in multiple reaction monitoring, with the transitions of 357.2 → 119.1, 373.1 → 150.1, 340.3 → 116.1, 361.1 → 138.1 and 343.2 → 116.1 m/z for pioglitazone, its hydroxyl metabolite, alogliptin, pioglitazone-d4 (IS-1) and alogliptin-d3 (IS-2), in order. Analysis was achieved within 4 min over a linear concentration range of 10-3000 ng/mL, 5-2000 ng/mL and 3-300 ng/mL, for pioglitazone, hydroxyl pioglitazone and alogliptin, in order. The method was fully validated according to FDA guidelines. The developed method was used for estimation of the three studied analytes in human plasma and pharmacokinetic parameters were demonstrated after oral dose administration of Oseni® tablets to Egyptian healthy volunteers.


Assuntos
Cromatografia Líquida/métodos , Pioglitazona/sangue , Piperidinas/sangue , Espectrometria de Massas em Tandem/métodos , Uracila/análogos & derivados , Humanos , Modelos Lineares , Pioglitazona/química , Pioglitazona/metabolismo , Pioglitazona/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Uracila/sangue , Uracila/química , Uracila/farmacocinética
18.
Drug Dev Ind Pharm ; 45(12): 1921-1930, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31625774

RESUMO

Objective: Repaglinide is a well-known FDA approved drug from category of meglitinide; used for the treatment of diabetes. However, its use is limited because of its poor water solubility which leads to erratic drug absorption. Present work focuses on formulation and evaluation of polyvinyl alcohol (PVA)-polyvinyl pyrrolidone (PVP) nanofibers to counter this problem of poor water solubility.Significance: Prepared nanofibers with hydrophilic polymers were expected to tackle the problem of poor water solubility.Methods: Nanofibers were prepared by electrospinning technique with the optimization of parameters affecting final product. Further prepared formulation was characterized using various techniques.Results: Successful development of drug loaded nanofibers was commenced utilizing electrospinning technique. Further casted film of same polymeric blend was prepared and compared with nanofibers. Optimized nanofibers showed an average diameter of 600-800 nm with smooth surface morphology. Prepared nanofibers and casted film was analyzed in terms of surface morphology, mechanical strength, solid state of drug present, effects of hydrogen bond formation and drug release profile. Results from the glucose tolerance test suggested both the formulations to be having better control over glucose levels as compared to free drug.Conclusion: Overall developed nanofibers presented themselves to be potential drug delivery candidates for drugs having poor water solubility.


Assuntos
Carbamatos/farmacocinética , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Hipoglicemiantes/farmacocinética , Nanofibras/química , Piperidinas/farmacocinética , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Carbamatos/administração & dosagem , Carbamatos/química , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Teste de Tolerância a Glucose , Interações Hidrofóbicas e Hidrofílicas , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Modelos Animais , Piperidinas/administração & dosagem , Piperidinas/química , Álcool de Polivinil/química , Povidona/química , Ratos , Solubilidade , Propriedades de Superfície
19.
Radiology ; 293(3): 695-703, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31617791

RESUMO

Background Transarterial chemoembolization with cytotoxic drugs is standard treatment for unresectable intermediate-stage hepatocellular carcinoma but achieves suboptimal outcomes because of hypoxic stress and the production of detrimental proangiogenic factors. An alternative approach using radiopaque embolization beads loaded with the antiangiogenic drug vandetanib may provide improved anticancer efficacy. Purpose To evaluate the pharmacokinetics, safety, and efficacy of vandetanib-eluting radiopaque bead (VERB) chemoembolization of rabbit liver tumors. Materials and Methods Between April 2015 and March 2016, 60 New Zealand white rabbits with VX2 liver tumors were randomly treated with VERBs at different doses, with nonloaded radiopaque beads (ROBs), or with intra-arterial vandetanib suspension (VS) or were not treated. Vandetanib plasma concentration and tumor growth at US were evaluated. Animals were euthanized after 3 days or 3 weeks. Assessment included bead distribution at x-ray imaging and histologic examination, tumor viability at histologic examination, and vandetanib tissue concentration. Group comparison analysis (Mann-Whitney, Kruskal-Wallis, and χ2 tests) and predictive factor analysis for tumor growth and viability were performed. Results Vandetanib plasma concentration was lower with VERBs than with VS (P < .01), while concentration in tumor was higher for VERBs (than for VS) at 3 days (median, 29.2 vs 2.74 ng/mg; P = .48). Tumor growth was lower with VERBs than with ROBs and with VS at both time points, with median values of +114%, +192%, and +466% at 3 weeks, respectively. Tumor viability was lower at 3 days for VERBs than for ROBs and for VS (3%, 18%, and 38%, respectively) but was not significantly different at 3 weeks. The volume of bead in tumor was a significant predictive factor for lower tumor growth in multivariable analysis at 3 days (P = .03). Drug tumor concentration was a significant predictive factor for lower tumor growth at 3 weeks (P = .04). Conclusion Vandetanib-eluting radiopaque bead chemoembolization showed a pharmacokinetic advantage over intra-arterial drug administration in a preclinical model of liver cancer. High deposition of beads and high vandetanib concentration in tumor led to stronger antitumor effects. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kim and Van den Abbeele in this issue.


Assuntos
Quimioembolização Terapêutica , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Piperidinas/farmacologia , Quinazolinas/farmacologia , Animais , Tomografia Computadorizada de Feixe Cônico , Microesferas , Piperidinas/farmacocinética , Quinazolinas/farmacocinética , Coelhos
20.
Expert Opin Drug Metab Toxicol ; 15(10): 849-867, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566028

RESUMO

Introduction: Piperine, the major bioactive component from black pepper, has gained increasing attention for its beneficial effects in the central nervous system (CNS). However, its related pharmacodynamics and brain pharmacokinetics, as well as its interaction with other CNS drugs are lacking, which may hinder its therapeutic and safe use. Areas covered: The current review provides an updated summary on CNS activities of piperine, including anti-epileptic, anti-depressive and neurodegeneration protection effect. The brain pharmacokinetic properties of piperine together with the approaches to enhance its aqueous solubility were summarized. Considering the wide use of black pepper and the well-reported alteration on CYP and transporters by piperine, interactions between piperine and CNS drugs are also illustrated for the first time. Expert opinion: Although the CNS beneficial effects of piperine have been extensively studied in preclinical models, clinical evidence on its CNS application is barely available, which may be attributed to its limited aqueous solubility, unclear pharmacokinetic properties in humans and potential toxicities during long-term use at higher doses. Although beneficial interactions between piperine and certain CNS drugs were often reported in preclinical studies, more mechanistic studies with clinically relevant doses should be conducted to provide guidance on their clinical combination use.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacocinética , Animais , Benzodioxóis/isolamento & purificação , Benzodioxóis/farmacocinética , Fármacos do Sistema Nervoso Central/isolamento & purificação , Fármacos do Sistema Nervoso Central/farmacocinética , Fármacos do Sistema Nervoso Central/farmacologia , Doenças do Sistema Nervoso Central/fisiopatologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Piperidinas/isolamento & purificação , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/isolamento & purificação , Alcamidas Poli-Insaturadas/farmacocinética
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