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1.
Am J Vet Res ; 67(1): 145-51, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16426224

RESUMEN

OBJECTIVE: To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma. ANIMALS: 23 dogs with lymphoma in stages IIIa, IVa, and Va. PROCEDURE: Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids. Serum doxorubicin and doxorubicinol concentrations were measured via high-performance liquid chromatography before and 6 to 9 weeks after initiation of the diets. Lymph node concentrations of doxorubicin were assessed 6 hours after the initial treatment. Dogs' body composition was assessed by means of dual-energy x-ray absorptiometry scans. RESULTS: No significant differences in doxorubicin pharmacokinetics were detected between treatment groups. Significant differences existed between the first and second sampling times among all dogs for area under the curve, maximum serum concentration, and clearance. Differences in body composition did not affect measured pharmacokinetic variables. The terminal elimination half-life was longer in dogs in which a long-term remission was achieved than in dogs that did not have remission. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary supplementation of n-3 fatty acids is common in veterinary patients with neoplasia, but supplementation did not affect doxorubicin pharmacokinetics in this population of dogs. Explanations for the beneficial effects of n-3 fatty acids other than alterations in the pharmacokinetics of chemotherapy drugs should be investigated. Dogs may metabolize drugs differently prior to remission of lymphoma than when in remission. The pharmacokinetics of doxorubicin at the time of the first administration may predict response to treatment.


Asunto(s)
Suplementos Dietéticos , Enfermedades de los Perros/metabolismo , Doxorrubicina/farmacocinética , Ácidos Grasos Omega-3/metabolismo , Linfoma/veterinaria , Animales , Cromatografía Líquida de Alta Presión , Enfermedades de los Perros/tratamiento farmacológico , Perros , Doxorrubicina/sangre , Doxorrubicina/uso terapéutico , Ácidos Grasos Omega-3/farmacología , Semivida , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Factores de Tiempo
2.
J Clin Oncol ; 23(34): 8786-93, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16246975

RESUMEN

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non-small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment. PATIENTS AND METHODS: Patients with tumor evidence of EGFR by immunohistochemistry, performance status of 0 to 2, and measurable disease received paclitaxel 225 mg/m2 with carboplatin area under the curve = 6 on day 1 every 3 weeks. Cetuximab was administered at 400 mg/m2, 1 week before paclitaxel and carboplatin, then weekly at 250 mg/m2. The regimen continued until disease progression or intolerable toxicity. RESULTS: Thirty-one of 32 enrolled patients were treated. The most common cetuximab toxicity was rash in 84% of patients (grade 3 in 13%). Pharmacokinetic sampling did not reveal an interaction between carboplatin, paclitaxel, and cetuximab. An objective response was observed in eight patients (26%). With a median follow-up of 19 months, the median time to progression was 5 months, median survival was 11 months, and the 1- and 2-year survival rates were 40% and 16%, respectively. CONCLUSION: The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated in this population of stage IV patients. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone. A randomized phase II trial has completed accrual.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cetuximab , Relación Dosis-Respuesta a Droga , Receptores ErbB/metabolismo , Exantema/inducido químicamente , Fatiga/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
3.
J Pharm Biomed Anal ; 39(3-4): 705-11, 2005 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-15935603

RESUMEN

ZD6474 (N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine) is a tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activity that is currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in clinical development of this agent to relate pre-clinical models to patient treatment. A liquid chromatography tandem mass spectrometry method was developed for the determination of ZD6474 levels in mouse plasma and tissues. Plasma (0.05 mL) and tissue homogenates (0.1 mL of 10 mg/mL) were extracted under alkaline conditions with ethyl acetate:pentane (1:1, v/v) after addition of the internal standard (trazodone, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one). Separation was achieved on a C18, 50 mm x 2 mm column with quantitation by internal standard reference and multiple reaction monitoring of the ion transitions m/z 475-->112 (ZD6474) and m/z 372-->176 (trazodone). The calibration curve was linear from a range spanning 20-20,000 ng/mL in plasma and 10-320 ng/mg in tissue homogenates. Mean recoveries from plasma and tissue homogenates were 88 and 90%, respectively. The accuracy in plasma was 88% at the lower limit of quantitation (20 ng/mL with a 50 microL plasma sample) with high precision (R.S.D.%<10%). Assay performance in liver and other tissue homogenates is also reported. The assay was applied to a pharmacokinetic study in mice to determine dosing schedules that would approximate therapeutic ZD6474 levels determined in humans.


Asunto(s)
Química Farmacéutica/métodos , Cromatografía Liquida/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Espectrometría de Masas/métodos , Neoplasias/tratamiento farmacológico , Piperidinas/análisis , Piperidinas/farmacocinética , Quinazolinas/análisis , Quinazolinas/farmacocinética , Acetatos/análisis , Animales , Antineoplásicos/farmacología , Calibración , Cromatografía/métodos , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Iones , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Químicos , Pentanos/análisis , Piperidinas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores de Tiempo , Distribución Tisular , Trazodona/análisis
4.
Cancer Chemother Pharmacol ; 56(3): 248-54, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15856231

RESUMEN

PURPOSE: Paclitaxel (Taxol) is an effective agent against a broad range of human cancers. Studies on the metabolism and disposition of paclitaxel have shown that it is primarily eliminated via hepatic metabolism by P450 enzymes (2C8 and 3A4) to essentially inactive metabolites, and that biliary and gut transport by P-glycoprotein (PGP) as well as urinary elimination of the parent compound play relatively minor roles. Recent studies in vitro have shown that paclitaxel treatment increases the level of CYP2C8 and CYP3A4 in human hepatocytes as well as PGP in colon tumor cells. The data suggest that previous paclitaxel exposure may influence metabolism and elimination of subsequent doses. Further, since weekly paclitaxel dose schedules are becoming more common as opposed to the original every 21-day dosing, the likelihood of enzyme induction from previous doses impacting that from subsequent doses is increased. METHODS: To study the potential for such sequence-dependent alterations in paclitaxel pharmacokinetics, we carried out pharmacokinetic studies in mouse plasma and tissues following day 1 and days 1 and 5 dosing at 20 mg/kg. Paclitaxel concentrations were determined by a sensitive LC/MS/MS assay out to 16 h post-dosing in plasma, liver, kidney, gut and heart. The effect of paclitaxel treatment on hepatic expression of PGP and P450 isoforms (CYP2C and CYP3A) was determined to elucidate the mechanism by which paclitaxel disposition is altered by previous drug exposure. RESULTS: Pharmacokinetic analysis of the data showed that plasma and tissue AUC values after treatment on day 5 following a dose on day 1 were between 50% and 74% of those determined following a single dose on day 1. The terminal elimination half-life was not different. Activity and protein levels for CYP2C in liver were elevated at 24 and 96 h after paclitaxel dosing. Cremophor EL, a carrier solvent for paclitaxel, also caused elevated CYP2C activity. Neither CYP3A nor PGP levels in liver were altered by paclitaxel or Cremophor EL treatment at the 24-h and 96-h time points. The levels of 6alpha-OH-paclitaxel in feces were increased on day 5 as opposed to day 1 while paclitaxel levels in feces were unchanged. CONCLUSIONS: The results of our studies showed that paclitaxel pharmacokinetics are altered by previous paclitaxel exposure up to 96 h earlier.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Sistema Enzimático del Citocromo P-450/biosíntesis , Paclitaxel/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Área Bajo la Curva , Citocromo P-450 CYP3A , Inducción Enzimática , Femenino , Semivida , Inyecciones Intravenosas , Hígado/efectos de los fármacos , Hígado/enzimología , Ratones , Ratones Endogámicos BALB C , Distribución Tisular
5.
Cancer Lett ; 220(2): 161-9, 2005 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-15766591

RESUMEN

Doxorubicin (DOX) has excellent antitumor activity when combined with paclitaxel (PTX) and this combination is used as first-line treatment for metastatic breast cancer. Results from clinical studies on pharmacokinetic interaction of these agents are not conclusive and pre-clinical studies are still needed. Pharmacokinetic studies were carried out in female Balb/c mice with combined DOX (6 mg/kg) and PTX (10 mg/kg) treatment. Combined treatment with PTX and DOX leads to alterations in the pharmacokinetics of both agents, with the predominant effect being elevated drug levels in liver and gut tissues. DOX levels in kidney and heart tissues were unaffected by concurrent PTX treatment. Further, plasma levels of DOX are not changed by concurrent PTX treatment suggesting that monitoring of plasma levels of DOX, when used in combination with another drug that is a P-glycoprotein (PGP) substrate, will not reflect actual pharmacokinetic changes occurring in other tissues.


Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Fitogénicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Animales , Neoplasias de la Mama/tratamiento farmacológico , Interacciones Farmacológicas , Femenino , Hígado/química , Ratones , Ratones Endogámicos BALB C , Distribución Tisular
6.
Clin Cancer Res ; 10(21): 7229-37, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15534096

RESUMEN

PURPOSE: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study. EXPERIMENTAL DESIGN: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150-250 mg) given orally twice daily and docetaxel (30-36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle. RESULTS: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed. CONCLUSIONS: The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sulindac/análogos & derivados , Sulindac/administración & dosificación , Sulindac/farmacocinética , Taxoides/administración & dosificación , Taxoides/farmacocinética , Adulto , Anciano , Antineoplásicos Fitogénicos/farmacocinética , Apoptosis , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento
7.
Cancer Chemother Pharmacol ; 52(2): 159-66, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12759775

RESUMEN

PURPOSE: Docetaxel is a semisynthetic taxane derived from the needles of the European yew ( Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60-100 mg/m(2) by infusion every 3 weeks. Now weekly low-dose (30-36 mg/m(2)) regimens are being evaluated in phase I trials. Such low-dose studies require a more sensitive, specific and rapid assay of docetaxel in biological fluids for the determination of pharmacokinetic parameters. Because docetaxel is primarily metabolized by CYP3A4 and is highly protein-bound in the plasma, there is potential for drug-drug interactions and high interpatient variability in pharmacokinetics. Therefore, pharmacokinetic studies are an important component to understanding the therapeutic variability of docetaxel-containing chemotherapeutic regimens. METHODS: To this end, we developed an analytical assay for docetaxel based upon tandem LCMS and paclitaxel as an internal standard. The sensitivity of the new assay allowed us to monitor plasma levels of docetaxel out to 48 h after the end of the infusion in patients enrolled in a phase I trial of exisulind (orally, twice daily) receiving weekly docetaxel doses of 30 or 36 mg/m(2) where plasma docetaxel levels are below the lower limit of quantitation for traditional HPLC/UV-based assays at later time-points. RESULTS: The inclusion of the 48-h time-point had significant effects on the calculated pharmacokinetic parameters when using either a three-compartment or non-compartmental analysis. The terminal half-life was significantly increased when the 48-h time-point was included in the pharmacokinetic analysis, and the use of model parameters derived with the inclusion of the 48-h time-point were able to more accurately predict plasma levels at later times. CONCLUSIONS: The results reflect the importance of accurate and sensitive analytical methods for the determination of pharmacokinetic parameters and the effect of this later time-point on docetaxel pharmacokinetic modeling. Further, with the increased use of weekly docetaxel in combination with other agents, the inclusion of these later sampling time-points and sensitive methods for drug level determinations are important components in the description of pharmacokinetic drug interactions.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias/metabolismo , Paclitaxel/análogos & derivados , Paclitaxel/farmacocinética , Taxoides , Antineoplásicos Fitogénicos/sangre , Área Bajo la Curva , Cromatografía Liquida , Docetaxel , Semivida , Humanos , Infusiones Intravenosas , Espectrometría de Masas , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Paclitaxel/sangre , Reproducibilidad de los Resultados , Manejo de Especímenes , Factores de Tiempo
8.
Toxicol Sci ; 73(2): 301-14, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12700395

RESUMEN

A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase pi (GST-P) enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen for 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TECB), pentachlorobenzene (PECB), and hexachlorobenzene (HCB). Male Fisher 344 rats, eight weeks of age, were initiated with a single dose (200 mg/kg, ip) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.1 mol/kg chlorobenzene was maintained for six weeks. Partial hepatectomy was performed three weeks after initiation. Liver weight, normal hepatocyte division rates, and the number and volume of GST-P positive foci were obtained at 23, 26, 28, 47, and 56 days after initiation. A clonal growth stochastic model separating the initiated cell population into two distinct subtypes (referred to as A and B cells) was successfully used to describe the foci development data for the four chlorobenzenes. The B cells are initiated cells that display a selective growth advantage under conditions that inhibit the growth of initiated A cells or normal hepatocytes. The simulation exercise for the four chlorobenzenes indicates a positive correlation between the estimated net growth rate of B cells during the 2-week regeneration period following partial hepatectomy and final foci volume at the end of the bioassay. This observation is consistent with the sensitivity analysis of model parameters. While TECB, PECB, and HCB all significantly increased foci volume, only HCB increased normal hepatocyte proliferation. Together, these results indicate that examining effects of chemicals on regenerative responses following partial hepatectomy may be a means for understanding the carcinogenicity potential of chlorobenzene compounds.


Asunto(s)
Carcinógenos/toxicidad , Clorobencenos/toxicidad , Hiperplasia Nodular Focal/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Lesiones Precancerosas/inducido químicamente , Administración Oral , Animales , Pruebas de Carcinogenicidad , Carcinógenos/administración & dosificación , Clorobencenos/administración & dosificación , Células Clonales , Simulación por Computador , Dietilnitrosamina/toxicidad , Quimioterapia Combinada , Hiperplasia Nodular Focal/enzimología , Hiperplasia Nodular Focal/patología , Glutatión Transferasa/metabolismo , Hepatectomía , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Lesiones Precancerosas/patología , Ratas , Ratas Endogámicas F344
9.
J Pharmacol Exp Ther ; 305(3): 1079-86, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12649308

RESUMEN

The bioreductive activation of the antitumor quinone mitomycin C (MMC) by NAD(P)H: quinone oxidoreductase 1 (NQO1) is complicated by the ability of MMC to also act as a mechanism-based inhibitor of NQO1 in a pH dependent manner. Inhibition of NQO1 by MMC has been studied in purified enzyme preparations and in cultured cells but has not determined in vivo. In the studies presented here, NQO1 activity was measured in mouse tissues following treatment with MMC or the potent mechanism-based human NQO1 inhibitor 5-methoxy-1,2-dimethyl-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936). NQO1 activity was significantly decreased at 1, 2, and 4 h following MMC (10 or 20 mg/kg) treatment in kidney and lung but was unchanged in brain, heart, liver, and bladder. ES936 (1 mg/kg) treatment led to a significant and much more potent inhibition of NQO1 in all murine tissues analyzed except for bladder. To extrapolate these in vivo results from mice to humans, the species-specific kinetics of NQO1 inactivation by MMC was determined in vitro using mouse, rat, and human recombinant NQO1 proteins. Results showed the inactivation kinetics of mouse and human proteins by MMC were similar. Treatment of human and murine endothelial cells with MMC or ES936 showed similar inhibition of NQO1 activity. The aforementioned results clearly demonstrate that MMC can serve as a substrate for NQO1 in vivo; however, the metabolism resulting in enzyme inactivation is possibly tissue-specific. Furthermore, the kinetic similarities for inactivation between murine and human forms of NQO1 show these results are apropos to clinical use of MMC.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Indolquinonas , Mitomicina/farmacología , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , Animales , Interacciones Farmacológicas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Humanos , Indoles/farmacología , Cinética , Ratones , Ratones Endogámicos BALB C , Ratas , Especificidad de la Especie , Células Tumorales Cultivadas
10.
J Pharm Sci ; 91(6): 1488-501, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12115848

RESUMEN

The studies described herein were designed to determine whether doxorubicin (DOX) pharmacokinetics (PKs) could be described by a physiologically based PK model that incorporated macromolecule-specific binding and organ-specific metabolism and excretion. Model parameters were determined experimentally, or were gathered from the literature, in a species-specific manner, and were incorporated into a physiologically based description of DOX blood and tissue distribution for mice, dogs, and humans. The resulting model simulation data were compared with experimentally determined data using PK parameters calculated using compartmental or noncompartmental analysis to assess the predictability of the models. The resulting physiologically based PK model that was developed could accurately predict blood and tissue PKs of DOX in mice. When this model was interspecies extrapolated to predict DOX levels in dogs and humans undergoing treatment for cancer, predictions in dog plasma or human serum were also consistent with the actual clinical data. This model has potential utility for predicting the magnitude of PK interactions of DOX with other drugs, and for predicting changes in DOX PKs in any number of clinical situations.


Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Linfoma/metabolismo , Modelos Animales , Animales , Sitios de Unión , Simulación por Computador , Modelos Animales de Enfermedad , Perros , Femenino , Humanos , Ratones , Modelos Biológicos
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