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1.
Drug Metab Dispos ; 44(5): 617-23, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26669328

RESUMEN

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Inmunoconjugados/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Industria Farmacéutica/métodos , Humanos
2.
Bioorg Med Chem Lett ; 26(2): 551-555, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26642765

RESUMEN

The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Dicetopiperazinas/síntesis química , Dicetopiperazinas/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Células CACO-2 , Estrona/análogos & derivados , Estrona/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/sangre , Humanos , Ratas , Estereoisomerismo , Relación Estructura-Actividad
3.
Int J Cancer ; 131(11): 2693-703, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-22488249

RESUMEN

Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy and pharmacodynamics of alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we report that alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established, suggesting that Aurora A inhibition may be a promising strategy to increase the efficacy of ara-C. Accordingly, alisertib significantly potentiated the antileukemic activity of ara-C in both AML cell lines and primary blasts. Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the alisertib/ara-C combination, indicating that it is an important regulator of sensitivity to these agents. In vivo studies demonstrated that alisertib significantly augmented the efficacy of ara-C without affecting its pharmacokinetic profile and led to the induction of p27 and BIM. Our collective data indicate that targeting Aurora A with alisertib represents a novel approach to increase the efficacy of ara-C that warrants further investigation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Azepinas/farmacología , Citarabina/farmacología , Factores de Transcripción Forkhead/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Aurora Quinasa A , Aurora Quinasas , Proteína 11 Similar a Bcl2 , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Sinergismo Farmacológico , Femenino , Proteína Forkhead Box O3 , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones SCID , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Bioorg Med Chem Lett ; 20(16): 4800-4, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20634068
5.
Expert Opin Drug Metab Toxicol ; 1(4): 595-611, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16863427

RESUMEN

Breast cancer resistance protein (BCRP), also known as ABCG2, ABCP and MXR, is a member of the ATP-binding cassette transporter G family. BCRP functions as a biological barrier that extrudes xenobiotics out of cells. The broad substrate specificity and tissue distributions of BCRP in the body make this transporter one of the major efflux transporters in chemotherapy. Recent studies have demonstrated that BCRP exerts a great impact on drug absorption and disposition. This review focuses on the role of BCRP in pharmacokinetics as well as in vitro and in vivo strategies to evaluate hepatic/intestinal BCRP-mediated drug transports and drug-drug interactions. The impacts of polymorphism and gender difference of BCRP are also discussed.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/fisiología , Interacciones Farmacológicas , Proteínas de Neoplasias/fisiología , Farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/análisis , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/genética , Absorción , Área Bajo la Curva , Barrera Hematoencefálica , Interacciones Alimento-Droga , Humanos , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Polimorfismo Genético
6.
Drug Metab Lett ; 7(2): 96-104, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24484538

RESUMEN

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.


Asunto(s)
Antineoplásicos/farmacocinética , Aurora Quinasa A/antagonistas & inhibidores , Azepinas/farmacocinética , Cálculo de Dosificación de Drogas , Evaluación Preclínica de Medicamentos , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Aurora Quinasa A/metabolismo , Azepinas/administración & dosificación , Azepinas/sangre , Células CACO-2 , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Perros , Femenino , Células HCT116 , Semivida , Humanos , Infusiones Subcutáneas , Hígado/metabolismo , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , Ratones Desnudos , Modelos Animales , Pan troglodytes , Unión Proteica , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Ratas Sprague-Dawley , Especificidad de la Especie , Ensayos Antitumor por Modelo de Xenoinjerto
7.
J Med Chem ; 54(6): 1836-46, 2011 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-21341678

RESUMEN

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.


Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Drug Metab Lett ; 4(4): 201-12, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20670210

RESUMEN

Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematological tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approximately a seven-fold increase in the mean plasma area under the concentration-versus-time curve (AUC) compared to the vehicle control group. In mice, after intravenous administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, respectively. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clinically.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/genética , Acridinas/farmacología , Administración Oral , Animales , Transporte Biológico , Encéfalo/metabolismo , Células CACO-2 , Humanos , Inyecciones Intravenosas , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas de Neoplasias/antagonistas & inhibidores , Piperazinas/administración & dosificación , Piperazinas/sangre , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Quinazolinas/administración & dosificación , Quinazolinas/sangre , Ratas , Ratas Sprague-Dawley , Tetrahidroisoquinolinas/farmacología , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
9.
Pharm Res ; 24(8): 1490-500, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17404811

RESUMEN

PURPOSE: To evaluate the expression, localization, function, and regulation of multidrug resistance protein (MRP1) in rabbit conjunctival epithelial cells (RCEC). MATERIALS AND METHODS: MRP1 gene expression in RCEC was determined by reverse transcription-polymerase chain reaction (RT-PCR), and MRP1 protein expression and its localization were determined by Western blot analysis and immunofluorescence using an anti-MRP1 monoclonal antibody, MRPr1. The effect of MRP1 on the transport and uptake of fluorescein was evaluated in RCEC grown on Transwell filters. Moreover, the effect of adenovirus type 5 (Ad5)-infected RCEC, and cytokines (Interleukin 1 (IL-1), IL-6, and tumor necrosis factor alpha (TNFalpha)) on MRP1 expression and leukotriene C4 (LTC4) uptake were investigated. RESULTS: A 652 bp RT-PCR product from rabbit conjunctiva showed a 87% homology to human MRP1. Immunostaining with MRPr1 revealed a predominant basolateral localization of MRP1 in RCEC. Uptake of fluorescein, a MRP1 substrate, was increased (203-290%) in the presence of uricosuric drug probenecid at 100 microM, anti-inflammatory drug indomethacin at 10 microM and diclofenac, flurbiprofen, and ofloxacin at 1 mM, and by ATP depletion, but not influenced by the depletion of GSH, and the presence of antiviral cidofovir and anti-inflammatory drug cromolyn and prednisolone. Apical-to-basolateral facilitated transport of LTC4 was abolished in the presence of probenecid. Western blot analysis with MRPr1 revealed a distinct band at approximately 190 kDa for freshly isolated and cultured RCEC. Both Ad5 and cytokines (IL-1, IL-6, and TNF-alpha) up-regulated MRP1 expression, thereby reducing LTC4 uptake. CONCLUSIONS: MRP1 appears to be primarily localized in the basolateral membrane of RCEC and function in the efflux of certain organic anions and inflammatory factors out of cells from the basolateral membrane. The upregulation in the expression of MRP1 by Ad5-infection and cytokines suggests a role of MRP1 in the transport of inflammatory factors during ocular inflammation. Supported by NIH grants EY12578, EY10421, and EY12356.


Asunto(s)
Conjuntiva/metabolismo , Células Epiteliales/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/fisiología , Preparaciones Farmacéuticas/metabolismo , Adenoviridae/crecimiento & desarrollo , Secuencia de Aminoácidos , Animales , Antiinflamatorios no Esteroideos/farmacología , Secuencia de Bases , Transporte Biológico Activo/efectos de los fármacos , Western Blotting , Butionina Sulfoximina/farmacología , Células CACO-2 , Células Cultivadas , Conjuntiva/citología , Citocinas/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Fluoresceína/metabolismo , Fluoresceína/farmacocinética , Expresión Génica/efectos de los fármacos , Humanos , Indometacina/farmacología , Leucotrieno C4/metabolismo , Leucotrieno C4/farmacocinética , Datos de Secuencia Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico
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