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1.
Xenobiotica ; 50(12): 1483-1489, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32623931

RESUMEN

Quercetin (QCN) is commonly used in high doses as a dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed through liquid chromatography-tandem mass spectrometry. The results showed a significant (p < 0.05) increase in exposure of QTE (peroral dosed) in the animals pre-treated with QCN as compared to the control group. All the animals pre-treated with QCN, succumbed to death within 3-5 min of intravenous dosing of QTE (1 mg/kg). The studies in rat liver S9 fraction indicated that QCN could increase the metabolic stability of QTE by inhibiting the activity of CYP enzymes. The brain to plasma ratio of QTE increased upon QCN pre-treatment (2.6 vs 7.7), which could be attributed to P-glycoprotein inhibition at the blood-brain barrier by QCN. The current set of studies indicated that serious herb-drug interaction between QCN and QTE might occur when they are co-administered. Caution is advised for concomitant use of QCN rich dietary supplements with QTE.


Asunto(s)
Quercetina/farmacocinética , Fumarato de Quetiapina/farmacocinética , Animales , Suplementos Dietéticos , Interacciones de Hierba-Droga , Ratas , Ratas Wistar
2.
Xenobiotica ; 50(10): 1258-1264, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32302241

RESUMEN

Aspirin (acetyl salicylic acid) is widely used co-medication in patients with cardiovascular and cerebrovascular diseases. Given the prevalence of acetyl salicylic acid's use as a co-medication and conflicting reports in the literature on it being a substrate of P-glycoprotein (P-gp). There is a potential risk for its interaction with compounds with P-gp liability, therefore, we have conducted a detailed investigation to determine substrate potential of acetyl salicylic acid towards P-gp. We observed significantly lower cellular uptake of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells compared to LLC-PK1 wild-type (WT) cells, however, the in vitro efflux of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells was not inhibited by known inhibitors under various conditions. Acetyl salicylic acid did not show active asymmetrical transport across MDR1 transfected LLC-PK1 cells compared to LLC-PK1-WT cells in transwell assay. Moreover, no difference in plasma and brain exposure of acetyl salicylic acid and its metabolite salicylic acid was observed between FVB-WT and Mdr1a/b knockout (KO) mice. Taken together, our findings indicate that acetyl salicylic acid is not a substrate of P-gp.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Aspirina/metabolismo , Animales , Transporte Biológico , Transporte Biológico Activo , Encéfalo , Células LLC-PK1 , Porcinos
3.
J Pharmacol Exp Ther ; 368(1): 136-145, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30361237

RESUMEN

Plasma pyridoxic acid (PDA) and homovanillic acid (HVA) were recently identified as novel endogenous biomarkers of organic anion transporter (OAT) 1/3 function in monkeys. Consequently, this clinical study assessed the dynamic changes and utility of plasma PDA and HVA as an initial evaluation of OAT1/3 inhibition in early-phase drug development. The study was designed as a single-dose randomized, three-phase, crossover study; 14 Indian healthy volunteers received probenecid (PROB) (1000 mg orally) alone, furosemide (FSM) (40 mg orally) alone, or FSM 1 hour after receiving PROB (40 and 1000 mg orally) on days 1, 8, and 15, respectively. PDA and HVA plasma concentrations remained stable over time in the prestudy and FSM groups. Administration of PROB significantly increased the area under the plasma concentration-time curve (AUC) of PDA by 3.1-fold (dosed alone; P < 0.05), and 3.2-fold (coadministered with FSM; P < 0.01), compared with the prestudy and FSM groups, respectively. The corresponding increase in HVA AUC was 1.8-fold (P > 0.05) and 2.1-fold (P < 0.05), respectively. The increases in PDA AUC are similar to those in FSM AUC, whereas those of HVA are smaller (3.1-3.2 and 1.8-2.1 vs. 3.3, respectively). PDA and HVA renal clearance (CL R) values were decreased by PROB to smaller extents compared with FSM (0.35-0.37 and 0.67-0.73 vs. 0.23, respectively). These data demonstrate that plasma PDA is a promising endogenous biomarker for OAT1/3 function and that its plasma exposure responds in a similar fashion to FSM upon OAT1/3 inhibition by PROB. The magnitude and variability of response in PDA AUC and CL R values between subjects is more favorable relative to HVA.


Asunto(s)
Proteína 1 de Transporte de Anión Orgánico/fisiología , Transportadores de Anión Orgánico Sodio-Independiente/fisiología , Ácido Piridóxico/sangre , Adolescente , Adulto , Biomarcadores/sangre , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto Joven
4.
J Pharmacol Exp Ther ; 358(3): 397-404, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27317801

RESUMEN

In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.


Asunto(s)
Coproporfirinas/sangre , Coproporfirinas/orina , Transportadores de Anión Orgánico/antagonistas & inhibidores , Rifampin/farmacología , Rosuvastatina Cálcica/farmacología , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Rifampin/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto Joven
5.
J Med Chem ; 64(5): 2339-2381, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33617716

RESUMEN

In the present work, we report compilation and analysis of 245 drugs, including small and macromolecules approved by the U.S. FDA from 2015 until June 2020. Nearly 29% of the drugs were approved for the treatment of various types of cancers. Other major therapeutic areas of focus were infectious diseases (14%); neurological conditions (12%); and genetic, metabolic, and cardiovascular disorders (7-8% each). Itemization of the approved drugs according to the year of approval, sponsor, target, chemical class, major drug-metabolizing enzyme(s), route of administration/elimination, and drug-drug interaction liability (perpetrator or/and victim) is presented and discussed. An effort has been made to analyze the pharmacophores to identify the structural (e.g., aromatic, heterocycle, and aliphatic), elemental (e.g., boron, sulfur, fluorine, phosphorus, and deuterium), and functional group (e.g., nitro drugs) diversity among the approved drugs. Further, descriptor-based chemical space analysis of FDA approved drugs and several strategies utilized for optimizing metabolism leading to their discoveries have been emphasized. Finally, an analysis of drug-likeness for the approved drugs is presented.


Asunto(s)
Aprobación de Drogas , Compuestos Orgánicos/uso terapéutico , Humanos , Compuestos Orgánicos/química , Estados Unidos , United States Food and Drug Administration
6.
ACS Med Chem Lett ; 12(3): 494-501, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33738077

RESUMEN

Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.

7.
ACS Med Chem Lett ; 12(7): 1143-1150, 2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34267885

RESUMEN

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

8.
Bioanalysis ; 12(15): 1049-1059, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32735140

RESUMEN

Aim: Our objective was to develop and qualify a bioanalytical method for the estimation of di-18:1-bis(monoacylglycero)phosphate (di-18:1 BMP) as a urinary biomarker for the assessment of drug-induced phospholipidosis and demonstrate its application in a preclinical study. Methodology/results: di-18:1 BMP was extracted by liquid-liquid extraction using n-butanol and analyzed by LC-MS/MS. The qualified method was selective, precise, robust and accurate across the linearity range (0.2-250 ng/ml). Qualified method was then used to assess chloroquine-induced phospholipidosis in rats dosed at 120 mg/kg for 5 days. A fivefold increase in di-18:1 BMP was observed on Day 5 compared with predose. Conclusion: Di-18:1 BMP can be used as a noninvasive biomarker to assess/screen compounds that could cause drug-induced phospholipidosis in rats.


Asunto(s)
Biomarcadores/orina , Cromatografía Liquida/métodos , Lisofosfolípidos/orina , Enfermedades por Almacenamiento Lisosomal/inducido químicamente , Monoglicéridos/orina , Fosfolípidos/metabolismo , Esfingolipidosis/inducido químicamente , Espectrometría de Masas en Tándem/métodos , Animales , Humanos , Enfermedades por Almacenamiento Lisosomal/orina , Masculino , Ratas , Ratas Sprague-Dawley , Esfingolipidosis/orina
9.
Biochem Pharmacol ; 79(4): 623-31, 2010 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19769946

RESUMEN

Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-alpha2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes.


Asunto(s)
Drogas en Investigación/farmacología , Indanos/farmacología , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Pirroles/farmacología , Animales , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Drogas en Investigación/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Indanos/síntesis química , Indanos/uso terapéutico , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ratones Transgénicos , Pirroles/síntesis química , Pirroles/uso terapéutico
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