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1.
Aquat Toxicol ; 230: 105714, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310674

RESUMO

Red Snapper (Lutjanus campechanus) were collected throughout the Gulf of Mexico (GoM) from 2011 to 2017 and analyzed for biliary (n = 496) fluorescent aromatic compounds (FACs), hepatic (n = 297) polycyclic aromatic hydrocarbons (PAHs) and microscopic hepatobiliary changes (MHC, n = 152). Gross and histological evaluations were conducted with liver tissues to identify and characterize pathological changes. This is the first report to interrelate hepatobiliary PAH concentrations and MHCs in Red Snapper. Hepatic PAHs measured in GoM Red Snapper ranged from 192 to 8530 ng g-1 w.w. and biliary FACs ranged from 480 to 1,100,000 ng FAC g-1 bile. Biliary FACs in Red Snapper collected along the west Florida Shelf and north central region declined after 2011 and were relatively stable until a sharp increase was noted in 2017. Increases in the PAH exposures are likely due to a number of sources including leaking infrastructure, annual spills, riverine input and the resuspension of contaminated sediments. In contrast, hepatic PAH concentrations were relatively stable indicating Red Snapper are able to maintain metabolic clearance however this energetic cost may be manifesting as microscopic hepatic changes (MHCs). Virtually all (99 %) of the evaluated Red Snapper had one to nine MHCs with an average of five coinciding changes in an individual fish. The observed changes were broadly classified as inflammatory responses, metabolic responses, degenerative lesions, nonneoplastic proliferation and neoplastic lesions. Biliary FACs were associated with parasitic infection and intracellular breakdown product accumulation such as intra-macrophage hemosiderin, lipofuscin and ceroid laden prevalence. Whereas, hepatic PAHs were associated with increased myxozoan plasmodia prevalence. This study evaluates relationships between hepatobiliary PAH concentrations and biometrics, somatic indices, condition factors and microscopic hepatic changes in Red Snapper located in the north central GoM. Together, these results may be signaling increased disease progression in Gulf of Mexico Red Snapper more than likely resulting from chronic environmental stressors including elevated PAH exposures and concentrations.


Assuntos
Bile/metabolismo , Monitoramento Ambiental/métodos , Fígado/efeitos dos fármacos , Fígado/patologia , Perciformes/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Florida , Golfo do México , Eliminação Hepatobiliar , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/análise , Prevalência , Poluentes Químicos da Água/análise
2.
J Pediatr ; 220: 245-248, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32111380

RESUMO

A hepatobiliary iminodiacetic acid (HIDA) scan is frequently used in an attempt to exclude biliary atresia in infants who are cholestatic. We present 6 cases of confirmed biliary atresia in infants who had biliary patency reported on HIDA scan. We demonstrate that misinterpreted HIDA scans led to delayed diagnosis and surgical intervention for biliary atresia.


Assuntos
Atresia Biliar/diagnóstico por imagem , Atresia Biliar/fisiopatologia , Eliminação Hepatobiliar , Iminoácidos , Sistema Biliar/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/diagnóstico por imagem , Masculino , Cintilografia , Estudos Retrospectivos
3.
Environ Sci Technol ; 54(2): 938-946, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31736300

RESUMO

Chlorinated paraffins (CPs) are chemicals with high production volumes that can accumulate at high levels in general populations. The pharmacokinetics of CPs as pollutants is unknown, and there is no evidence that the medium chain chlorinated paraffins (MCCPs) and long chain chlorinated paraffins (LCCPs) are safe replacements for short chain chlorinated paraffins (SCCPs). In this study, SCCPs, MCCPs, and LCCPs were first in vivo and in vitro exposed to rat and liver microsomes, respectively. Toxicokinetics of these compounds were assessed and used to establish the corresponding physiologically based pharmacokinetic (PBPK) models in rats. More than 90% of ingested CPs were deposited in the liver and fat, and the compounds were extremely resistant to metabolism and mostly eliminated via biliary excretion. Then, humans' external and internal exposures to CPs were investigated for one year in Shenzhen, South China. The results were used to calibrate the key parameters for the establishment of a PBPK model in humans. In the PBPK models of rats and humans, the rate of biliary excretion had the greatest influence on the accumulated levels and half-lives of CPs. The body half-lives of human were estimated to be 5.1, 1.2, and 0.6 years for SCCPs, MCCPs, and LCCPs, respectively, suggesting the high accumulation of SCCPs in humans compared to other CPs.


Assuntos
Eliminação Hepatobiliar , Hidrocarbonetos Clorados , Animais , China , Monitoramento Ambiental , Humanos , Parafina , Ratos
4.
Indian J Gastroenterol ; 38(5): 441-449, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31802440

RESUMO

BACKGROUND: The indocyanine green retention rate at 15 min (ICGR15) is a marker of the liver function and is useful for planning hepatectomy. To clarify the ICGR15 and the related clearance value (ICGK) calculated by a dye-dilution cardiac output flowmetry (DCOF), we examined the correlation and clinical significance of the ICGR15 values determined by DCOF and those determined with the conventional blood sampling (BS) procedure. METHODS: We extracted liver function parameters, including the ICGR15 modified value and ICGK, and the extent of hepatectomy from the clinical and surgical records of 63 patients with various liver diseases in whom the ICGR15 (actual value), R15m (mean), and K (clearance rate per minute) were measured by DCOF. RESULTS: All the patients were classified as Child-Pugh grade A. Hepatic complications were observed in 10 (16%) patients, but there was no mortality. The mean values of ICGR15 determined by BS (R15-BS) and DCOF (R15-DCOF) were 12.2 ± 8.1% and 11.2 ± 8.7%, respectively. The mean R15m determined by DCOF (R15m-DCOF) was 15.7 ± 10.2%. Significant differences were observed between R15-BS and R15-DCOF (1.1 ± 4.8%; p = 0.002) and R15m-DCOF (4.0 ± 5.9%; p < 0.001). The difference between R15-BS and R15m-DCOF was greater than that between R15-BS and R15-DCOF. Correlation between R15-BS and R15-DCOF was significant r = 0.839 (p < 0.001). CONCLUSIONS: The ICGR15 measured by DCOF shows comparable reliability and stability to the BS method, which is useful for planning hepatectomy.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Corantes/farmacocinética , Verde de Indocianina/farmacocinética , Testes de Função Hepática/métodos , Neoplasias Hepáticas/diagnóstico , Reologia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/cirurgia , Débito Cardíaco , Feminino , Hepatectomia , Eliminação Hepatobiliar , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Reprodutibilidade dos Testes , Reologia/métodos , Adulto Jovem
5.
Contrast Media Mol Imaging ; 2019: 1760184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787861

RESUMO

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Radioisótopos de Carbono , Indazóis , Proteínas de Neoplasias/análise , Fosfatidilinositol 3-Quinases/análise , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Sulfonamidas , Animais , Neoplasias da Mama/patologia , Radioisótopos de Carbono/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Eliminação Hepatobiliar , Xenoenxertos , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Indazóis/farmacologia , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Transplante de Neoplasias , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Transdução de Sinais , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Distribuição Tecidual
6.
Drug Metab Dispos ; 47(12): 1397-1402, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31563869

RESUMO

This study re-examined the hepatic extraction for diazepam, the only drug for which isolated perfused rat liver (IPRL) studies have been reported not to be consistent with the well stirred model of organ elimination when only entering and exiting liver concentration measurements are available. First, the time dependency of diazepam equilibrium fraction unbound measurements from 4 to 24 hours was tested, reporting the continuing increases with time. The results showed that the time dependency of equilibrium protein-binding measurements for very highly bound drugs may be an issue that is not readily overcome. When examining C out/C in (F obs) measurements for diazepam when no protein is added to the incubation media, IPRL outcomes were consistent with previous reports showing marked underpredictability of in vivo clearance from in vitro measures of elimination in the absence of protein for very highly bound drugs, which is markedly diminished in the presence of albumin. F obs for diazepam at additional low concentrations of protein that would allow discrimination of the models of hepatic elimination produced results that were not consistent with the dispersion and parallel-tube models. Therefore, although the outcomes of this study were similar to those reported by Rowland and co-workers, when no protein is added to the perfusion media, these IPRL results for diazepam cannot be reasonably interpreted as proving that hepatic organ elimination is model-independent or as supporting the dispersion and parallel-tube models of organ elimination. SIGNIFICANCE STATEMENT: The only drug experiments for which isolated perfusion rat liver studies do not support hepatic clearance being best described by the well stirred model have been carried out with diazepam at zero protein concentration. This study repeated those studies, confirming the previous results at zero protein concentration, but the addition of low protein-binding conditions capable of differentiating the various models of hepatic elimination are more consistent with the well stirred model of hepatic elimination. These experimental studies do not support the preference for alternate models of hepatic elimination or the proposal that hepatic organ clearance is model-independent.


Assuntos
Diazepam/metabolismo , Eliminação Hepatobiliar , Fígado/metabolismo , Modelos Biológicos , Albuminas/metabolismo , Animais , Técnicas In Vitro , Cinética , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Perfusão , Ligação Proteica , Ratos , Ratos Sprague-Dawley
7.
Biochem Pharmacol ; 169: 113596, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31398312

RESUMO

The liver is the most important drug metabolizing organ, endowed with a plethora of metabolizing enzymes and transporters to facilitate drug entry and removal via metabolism and/or biliary excretion. For this reason, much focus surrounds the development of clearance concepts, which are based on normalizing the rate of removal to the input or arterial concentration. By so doing, some authors have recently claimed that it implies one specific model of hepatic elimination, namely, the widely used well-stirred or venous equilibration model (WSM). This commentary challenges this claim and aims to provide a comprehensive discussion of not only the WSM but other currently applied hepatic clearance models - the parallel tube model (PTM), the dispersion model (DM), the zonal liver model (ZLM), and the heterogeneous capillary transit time model of Goresky and co-workers (GM). The WSM, PTM, and DM differ in the patterns of internal blood flow, assuming bulk, plug, and dispersive flows, respectively, which render different degrees of mixing within the liver that are characterized by the magnitudes of the dispersion number (DN), resulting in different implications concerning the (unbound) substrate concentration in liver (CuH). Early models assumed perfusion rate-limited distribution, which have since been modified to include membrane-limited transport. The recent developments associated with the misconceptions and the sensitivity of the models are hereby addressed. Since the WSM has been and will likely remain widely used, the pros and cons of this model relative to physiological reality are further discussed.


Assuntos
Eliminação Hepatobiliar/fisiologia , Hepatócitos/metabolismo , Fígado/metabolismo , Modelos Biológicos , Animais , Humanos , Taxa de Depuração Metabólica , Preparações Farmacêuticas/metabolismo , Ligação Proteica , Ratos , Distribuição Tecidual
8.
J Pharmacol Exp Ther ; 371(1): 151-161, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399494

RESUMO

Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating 14CO2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental physiologically based pharmacokinetic (PBPK) model was built for 14C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. 14CO2 production rates were simulated taking the first derivative of by-product 14CO2 concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control 14CO2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. SIGNIFICANCE STATEMENT: Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.


Assuntos
Dióxido de Carbono/metabolismo , Eritromicina/farmacocinética , Eliminação Hepatobiliar , Fígado/metabolismo , Modelagem Computacional Específica para o Paciente , Testes Respiratórios/métodos , Citocromo P-450 CYP3A/metabolismo , Humanos
9.
Congenit Heart Dis ; 14(6): 978-986, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31369200

RESUMO

BACKGROUND & AIMS: Fontan surgery for single ventricle congenital heart disease leads to Fontan-associated liver disease (FALD). Typical laboratory tests, imaging, and histopathology cannot predict clinical severity in FALD. HepQuant SHUNT is a proprietary serum test of hepatic function and physiology that has not yet been evaluated in FALD. METHODS: Fourteen adult FALD patients at a single urban tertiary care center who underwent a Fontan procedure in childhood received HepQuant SHUNT testing between September 2015 and April 2018. The HepQuant SHUNT disease severity index (DSI) assesses global liver function and physiology from systemic and portal hepatic filtration rates (HFRs, clearances adjusted for body mass) of orally and intravenously administered cholates labeled with deuterium or 13C. The SHUNT parameter of the test measures portal systemic shunting from the ratio of Systemic HFR to Portal HFR. Chart review included laboratory tests, imaging, and clinical findings. Data from FALD patients were compared with data from healthy controls. RESULTS: The average DSI and SHUNT values for the FALD patients were 17.5% and 36.1%, respectively, compared to 9.2% and 24.1%, respectively, for controls. Twelve (85.7%) FALD patients had a DSI >15 (upper limit of normal). Seven (50.0%) FALD patients had SHUNT values >30% (upper limit of normal), while three FALD patients (21.4%) had SHUNT values >49%. One FALD patient with preoperative SHUNT of 69%, who underwent a combined heart-liver transplant, had confirmed cirrhotic morphology within the liver explant. CONCLUSIONS: This pilot study demonstrated that most FALD patients had hepatic impairment detected by abnormal DSI, with a smaller number having markedly elevated SHUNT values >49% suggesting intrinsic liver disease. The HepQuant SHUNT test may be useful in detecting and quantifying liver disease severity in FALD patients.


Assuntos
Ácidos Cólicos/administração & dosagem , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Circulação Hepática , Hepatopatias/diagnóstico , Testes de Função Hepática , Administração Intravenosa , Adulto , Estudos de Casos e Controles , Ácidos Cólicos/sangue , Estudos Transversais , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Eliminação Hepatobiliar , Humanos , Hepatopatias/etiologia , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Índice de Gravidade de Doença , Adulto Jovem
10.
Cancer Biother Radiopharm ; 34(9): 551-558, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436470

RESUMO

Objectives: The epidermal growth factor receptor (EGFR) signaling pathway is widely recognized to play an important role in development and progression of many malignant tumors, including lung cancer. The aim of this study was to produce a useful technetium-99m (99mTc) complex for early detection and staging of EGFR-positive tumors. Methods: The authors labeled quinazoline derivative (3-iodinephenyl) quinazoline-4, 6-diamine with 99mTc using S-acetylmercaptoacetyltriglyglycinate (MAG3) conjugated to quinazoline derivative through 4-[(2-aminoethyl)amino]-4-oxobut-2-enoic acid because it is a bifunctional chelator with an average yield of 93.9% ± 2.5% and radiochemical purity of >98%. Results: In vitro studies indicate that the [99mTc]-complex13 has high stability in physiological conditions and binds the HCC 827 cells and shows HCC 827 internalization. The biodistribution of the [99mTc]-complex13 in healthy Institute of Cancer Research mice indicates the rather fast blood clearance through the hepatobiliary system. Conclusion: These preliminary results pave the road for estimating the status of EGFR and monitoring the response to EGFR tyrosine kinase inhibitors as a personalized cancer therapy regimen.


Assuntos
Receptores ErbB/metabolismo , Quinazolinas/química , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/química , Animais , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Receptores ErbB/antagonistas & inibidores , Eliminação Hepatobiliar , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quinazolinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Tecnécio/farmacocinética , Distribuição Tecidual
11.
Can J Physiol Pharmacol ; 97(11): 1080-1089, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31340129

RESUMO

An in vivo intestinal perfusion model was used to investigate how experimental hyperglycemia affects intestinal elimination and biliary excretion in the rat. Experimental diabetes was induced by administration of streptozotocin (65 mg/kg, i.v.). The intestinal perfusion medium contained 250 µM (±)-ibuprofen. An isocratic high-performance liquid chromatography method with UV-visible detection was developed to quantitate ibuprofen in the intestinal perfusate, while a gradient method was applied to quantitate ibuprofen and ibuprofen-ß-d-glucuronide in the bile. The limit of quantitation of ibuprofen was found to be 0.51 µM in the perfusate of the small intestine. In the bile, the limit of quantitation of ibuprofen and ibuprofen-ß-d-glucuronide was 4.42 and 10.3 µM, respectively. Unconjugated ibuprofen and ibuprofen-ß-d-glucuronide were detected in the bile; however, no ß-d-glucuronide of ibuprofen could be detected in the intestinal perfusate. The results indicate that experimental diabetes can cause a decrease in the disappearance of ibuprofen from the small intestine. Excretion of both ibuprofen and ibuprofen-ß-d-glucuronide decreased to the bile in experimental diabetes. The results can be explained by the results of molecular biological studies indicating streptozotocin-initiated alterations in the intestinal and hepatic transport processes.


Assuntos
Eliminação Hepatobiliar , Hiperglicemia/metabolismo , Ibuprofeno/farmacocinética , Eliminação Intestinal , Animais , Masculino , Ratos , Ratos Wistar
12.
Drug Metab Dispos ; 47(8): 899-906, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31160314

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is a common form of inherited polycystic kidney disease (PKD) and is a leading cause of kidney failure. Fluid-filled cysts develop in the kidneys of patients with ADPKD, and cysts often form in their liver and other organs. Previous data have shown that bile acids are increased in the liver of polycystic kidney (PCK) rats, a rodent model of PKD; these changes may be associated with alterations in liver transporter expression and function. However, the impact of PKD on hepatic transporters has not been characterized. Therefore, this preclinical study was designed to investigate hepatic transporter expression and function in PCK compared with wild-type (WT) Sprague-Dawley rats. Transporter gene expression was measured by quantitative polymerase chain reaction, and protein levels were quantified by Western blot and liquid chromatography-tandem mass spectroscopy (LC-MS/MS)-based proteomic analysis in rat livers. Transporter function was assessed in isolated perfused livers (IPLs), and biliary and hepatic total glutathione content was measured. Protein expression of Mrp2 and Oatp1a4 was decreased 3.0-fold and 2.9-fold, respectively, in PCK rat livers based on Western blot analysis. Proteomic analysis confirmed a decrease in Mrp2 and a decrease in Oatp1a1 expression (PCK/WT ratios, 0.368 ± 0.098 and 0.563 ± 0.038, respectively; mean ± S.D.). The biliary excretion of 5(6)-carboxy-2',7'-dichlorofluorescein, a substrate of Oatp1a1, Mrp2, and Mrp3, was decreased 28-fold in PCK compared with WT rat IPLs. Total glutathione was significantly reduced in the bile of PCK rats. Differences in hepatic transporter expression and function may contribute to altered disposition of Mrp2 and Oatp substrates in PKD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Eliminação Hepatobiliar , Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Rim Policístico Autossômico Dominante/metabolismo , Animais , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Fluoresceínas/metabolismo , Perfilação da Expressão Gênica , Glutationa/análise , Glutationa/metabolismo , Humanos , Masculino , Proteômica , Ratos
13.
Br J Clin Pharmacol ; 85(9): 2011-2021, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31112623

RESUMO

AIMS: The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated. METHODS: In this phase 1, open-label, nonrandomised, parallel-group, pharmacokinetic study, men and women with mild or moderate hepatic impairment (Child-Pugh grade A or B) and control participants with normal hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured. RESULTS: Thirty-six participants completed the study: 9 with mild hepatic impairment, 9 with moderate hepatic impairment and 18 matched control participants with normal hepatic function. Vilaprisan reached maximum plasma concentrations after 1-2 hours. Unbound vilaprisan exposure was 1.44-fold higher for participants with mild hepatic impairment vs controls (90% confidence interval: 0.91-2.26), and 1.74-fold higher for participants with moderate impairment vs controls (90% confidence interval: 1.09-2.78). The maximum observed unbound peak concentrations were similar for participants with hepatic impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment-emergent adverse events was similar across cohorts. CONCLUSION: Only mild increases of <1.75-fold in exposure were observed in participants with mild or moderate hepatic impairment compared with control participants. No safety concern was identified. These data, alongside the excellent safety profile observed in phase 1 and 2 studies, do not indicate that a dose adjustment would be required in patients with mild or moderate hepatic impairment.


Assuntos
Hepatopatias/fisiopatologia , Fígado/fisiopatologia , Esteroides/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Feminino , Eliminação Hepatobiliar/fisiologia , Humanos , Fígado/metabolismo , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/urina , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Esteroides/administração & dosagem , Adulto Jovem
14.
ACS Nano ; 13(5): 5785-5798, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30990673

RESUMO

Understanding how nanoparticles are eliminated from the body is required for their successful clinical translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that determined the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells ( e. g., Kupffer cells and liver sinusoidal endothelial cells) determines the elimination fate. Each step in the route contains cells that can sequester and chemically or physically alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is critical to engineering medically useful and translatable nanotechnologies.


Assuntos
Plásticos Biodegradáveis/química , Eliminação Hepatobiliar/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/química , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Plásticos Biodegradáveis/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Nanopartículas/metabolismo
15.
Toxicol Appl Pharmacol ; 372: 1-10, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978397

RESUMO

Previously, we developed a series of physiologically based pharmacokinetic (PBPK) models for manganese (Mn) in which saturable tissue binding and dose-dependent increases in biliary excretion captured key aspects of Mn homeostasis biology. These models reproduced the non-linear behavior of Mn kinetics in different tissues, accounting for dose-dependent changes in Mn kinetics. The original model construct had relatively slow association and dissociation rate constants for Mn binding in tissues. In this updated model, both rates of entry into tissue and the interaction of Mn with binding sites are rapid, and the step limiting Mn accumulation is the saturation of tissue binding sites. This binding reflects general cellular requirements for Mn with high affinity but rapid exchange between bound and free forms, which we captured using a dissociation constant (KD) of ~ 0.5 µM across tissues while maintaining different maximum binding capacities in each tissue. Variability in the binding capacities accounted for different background levels of Mn in particular tissues. This alternative structure successfully described Mn kinetics in tissues in adult rats exposed to Mn either in their diet or by inhalation, indicating that both the original and the present models capture the dose-dependent and tissue-specific kinetic behavior of Mn in adult rats. Although the published models that emphasize the role of smaller tissue binding rate constants in non-linear behaviors capture all relevant dose-dependent kinetic behaviors of this metal, increasing biological relevance of the model structure and parameters should provide greater confidence in applying the Mn PBPK models to risk assessment.


Assuntos
Manganês/farmacocinética , Modelos Biológicos , Animais , Transporte Biológico , Relação Dose-Resposta a Droga , Eliminação Hepatobiliar , Homeostase , Humanos , Manganês/toxicidade , Dinâmica não Linear , Ligação Proteica , Medição de Risco , Distribuição Tecidual , Toxicocinética
16.
Toxicon ; 162: 1-8, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849452

RESUMO

Microcystin-LR (MCLR) is a cyanotoxin produced by blue-green algae that causes liver and kidney toxicities. MCLR toxicity is dependent on cellular uptake through the organic anion transporting polypeptide (OATP) transporters. Nonalcoholic fatty liver disease (NAFLD) progresses through multiple stages, alters expression of hepatic OATPs, and is associated with chronic kidney disease. The purpose of this study was to determine whether NAFLD increases systemic exposure to MCLR and influences acute liver and kidney toxicities. Rats were fed a control diet or two dietary models of NAFLD; methionine and choline deficient (MCD) or high fat/high cholesterol (HFHC). Two studies were performed in these groups: 1) a single dose intravenous toxicokinetic study (20 µg/kg), and 2) a single dose intraperitoneal toxicity study (60 µg/kg). Compared to control rats, plasma MCLR area under the concentration-time curve (AUC) in MCD rats doubled, whereas biliary clearance (Clbil) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Clbil approximately doubled. Less MCLR bound to PP2A was observed in the liver of MCD rats. This shift in exposure decreased the severity of liver pathology only in the MCD rats after a single toxic dose of MCLR (60 µg/kg). In contrast, the single toxic dose of MCLR increased hepatic inflammation, plasma cholesterol, proteinuria, and urinary KIM1 in HFHC rats more than MCLR exposed control rats. In conclusion, rodent models of NAFLD alter MCLR toxicokinetics and acute toxicity and may have implications for liver and kidney pathologies in NAFLD patients.


Assuntos
Fígado/efeitos dos fármacos , Microcistinas/toxicidade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Moléculas de Adesão Celular/urina , Colesterol/metabolismo , Colina/metabolismo , Dieta Hiperlipídica , Eliminação Hepatobiliar , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Toxinas Marinhas , Metionina/deficiência , Microcistinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transportadores de Ânions Orgânicos/metabolismo , Proteína Fosfatase 2/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Ratos Sprague-Dawley , Toxicocinética
17.
Biomed Res Int ; 2019: 1212404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30868067

RESUMO

Introduction: Hydatidosis is a zoonotic infection and treatment is mandatory to avoid complications. Surgery remains the first choice in the treatment especially for CE2-CE3b cysts. Open or laparoscopic approaches are available. However, comparative studies are limited. Materials and Methods: Data of patients who underwent cystotomy/partial cystectomy for liver hydatidosis between January 2012 and September 2016 (n=77) were evaluated retrospectively. Recurrent cases and the patients with previous hepatobiliary surgery were excluded. 23 patients were operated upon laparoscopically and named as Group 1. 48 patients operated conventionally named as Group 2. Demographics, cyst characteristics, operative time, length of hospital stay, recurrences, and surgery related complications were evaluated. Results: Groups were similar in terms of demographics, cyst characteristics, and operative time. The length of hospital stay was 3.4 days in Group 1 and 4.7 days in Group 2 (p=0,007). The mean follow-up period was 17.8 months and 21.7 months, respectively (p=0.170). Overall complication rates were similar in two groups (p=0.764). Three conversion cases occurred (13%). One mortality was seen in Group 2. Four recurrences occurred in each group (17% versus 8.3%, respectively) (p=0.258). Conclusions: Laparoscopy is a safe and feasible approach for surgical treatment of liver hydatidosis. Recurrence may be prevented by selection of appropriate cases in which exposure of cysts does not pose an intraoperative difficulty.


Assuntos
Cistos/cirurgia , Equinococose/cirurgia , Fígado/cirurgia , Zoonoses/cirurgia , Adulto , Idoso , Animais , Cistotomia , Cistos/fisiopatologia , Equinococose/fisiopatologia , Feminino , Eliminação Hepatobiliar , Humanos , Laparoscopia , Tempo de Internação , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/fisiopatologia , Zoonoses/fisiopatologia
18.
Biomed Res Int ; 2019: 7604939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834274

RESUMO

Background: In inflammatory bowel disease (IBD) patients there are reports of the occurrence of hepatobiliary manifestations, so the aim of this study was to evaluate the hepatobiliary manifestations in patients with Crohn's disease (CD) and ulcerative colitis (UC) from an IBD reference center. Methods: Cross-sectional study in an IBD reference center, with interviews and review of medical charts, between July 2015 and August 2016. A questionnaire addressing epidemiological and clinical characteristics was used. Results: We interviewed 306 patients, and the majority had UC (53.9%) and were female (61.8%). Hepatobiliary manifestations were observed in 60 (19.6%) patients with IBD. In the greater part of the patients (56.7%) hepatobiliary disorders were detected after the diagnosis of IBD. In UC (18.2%) patients, the hepatobiliary disorders identified were 11 (6.7%) non-alcoholic fatty liver disease, 9 (5.5%) cholelithiasis, 6 (3.6%) primary sclerosing cholangitis (PSC), 3 (1.8%) hepatotoxicity associated with azathioprine, 1 (0.6%) hepatitis B, and 1 (0.6%) hepatic fibrosis. In CD (21.3%) patients, 11 (7.8%) had cholelithiasis, 11 (7.8%) non-alcoholic fatty liver disease, 4 (2.8%) PSC, 3 (2.1%) hepatotoxicity, 1 (0.7%) hepatitis B, (0.7%) hepatitis C, 1 (0.7%) alcoholic liver disease, and 1 (0.7%) autoimmune hepatitis (AIH). There was one case of PSC/AIH overlap syndrome. Conclusion: The frequency of hepatobiliary disorders was similar in both forms of IBD in patients evaluated. The most common nonspecific hepatobiliary manifestations in IBD patients were non-alcoholic liver disease and cholelithiasis. The most common specific hepatobiliary disorder was PSC in patients with extensive UC or ileocolonic CD involvement; this was seen more frequently in male patients.


Assuntos
Eliminação Hepatobiliar , Doenças Inflamatórias Intestinais/diagnóstico , Fígado/fisiopatologia , Adulto , Azatioprina/efeitos adversos , Colelitíase/diagnóstico , Colelitíase/fisiopatologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/diagnóstico , Doença de Crohn/fisiopatologia , Estudos Transversais , Feminino , Hepatite B/diagnóstico , Hepatite B/fisiopatologia , Hepatite C/diagnóstico , Hepatite C/fisiopatologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/fisiopatologia , Humanos , Doenças Inflamatórias Intestinais/classificação , Doenças Inflamatórias Intestinais/fisiopatologia , Hepatopatias/classificação , Hepatopatias/patologia , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Adulto Jovem
19.
Toxicol Sci ; 169(1): 167-179, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768125

RESUMO

2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%-94% in 24 h; 5% was recovered in feces; and 1%-2% in blood/tissues. TBP administered to female SD rats (0.1-1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%-27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.


Assuntos
Retardadores de Chama/administração & dosagem , Retardadores de Chama/farmacocinética , Fungicidas Industriais/administração & dosagem , Fungicidas Industriais/farmacocinética , Fenóis/administração & dosagem , Fenóis/farmacocinética , Administração Cutânea , Administração Oral , Animais , Bile/metabolismo , Disponibilidade Biológica , Biotransformação , Fezes/química , Feminino , Fungicidas Industriais/sangue , Fungicidas Industriais/urina , Eliminação Hepatobiliar , Humanos , Injeções Intravenosas , Eliminação Intestinal , Masculino , Camundongos , Modelos Biológicos , Fenóis/sangue , Fenóis/urina , Ratos , Ratos Sprague-Dawley , Eliminação Renal , Fatores Sexuais , Especificidade da Espécie , Distribuição Tecidual
20.
Oncologist ; 24(8): 1137-1145, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30710067

RESUMO

BACKGROUND: Vinorelbine has demonstrated anticancer activity and is primarily metabolized in the liver. This single-institution, phase I pilot study describes the safety and pharmacokinetics of vinorelbine in patients with varying degrees of hepatic impairment. MATERIALS AND METHODS: Patients with treatment-refractory solid tumors were enrolled into treatment arms based on vinorelbine dose (weekly infusions of 7.5-30 mg/m2) and liver function (normal liver function, mild, moderate, or severe liver dysfunction). Vinorelbine pharmacokinetics were evaluated to describe its relationship with liver function. Indocyanine green (ICG) clearance was assessed for correlation with pharmacokinetics. RESULTS: Forty-seven patients were enrolled, and a total of 108 grade 3-4 treatment-related adverse events (AEs) occurred. Of these, grade 3-4 myelosuppression was the most common (34.3%). Thirty-three (30.6%), 22 (20.4%), and 9 (8.3%) grade 3-4 AEs were observed in the vinorelbine 20 mg/m2/severe, 15 mg/m2/moderate, and 7.5 mg/m2/severe liver dysfunction groups, respectively, with the majority being nonhematologic toxicities. ICG clearance decreased as liver function worsened. Vinorelbine pharmacokinetics were not correlated with ICG elimination or the degree of liver dysfunction. CONCLUSION: For patients with severe liver dysfunction (bilirubin >3.0 mg/dL), vinorelbine doses ≥7.5 mg/m2 are poorly tolerated. The high incidence of grade 3-4 AEs with 15 mg/m2 vinorelbine in moderate liver dysfunction (bilirubin 1.5-3.0 mg/dL) raises concerns for its safety in this population. Vinorelbine pharmacokinetics are not affected by liver dysfunction; however, levels of the active metabolite 4-O-deacetylvinorelbine were not measured and may be higher in patients with liver dysfunction if its elimination is impacted by liver impairment to a greater degree than the parent drug. IMPLICATIONS FOR PRACTICE: Vinorelbine remains widely prescribed in advanced malignancies and is under development in immunotherapy combinations. Given vinorelbine is primarily hepatically metabolized, understanding its safety and pharmacokinetics in liver dysfunction remains paramount. In this phase I pilot study, weekly vinorelbine at doses ≥7.5 mg/m2 is poorly tolerated in those with severe liver dysfunction. Furthermore, a high incidence of grade 3-4 toxicities was observed with vinorelbine at 15 mg/m2 in those with moderate liver dysfunction. Vinorelbine pharmacokinetics do not appear affected by degree of liver dysfunction. Further evaluation of levels of the free drug and active metabolites in relationship to liver function are warranted.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hepatopatias/fisiopatologia , Neoplasias/tratamento farmacológico , Vinorelbina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Eliminação Hepatobiliar/fisiologia , Humanos , Incidência , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Índice de Gravidade de Doença , Vinorelbina/administração & dosagem , Vinorelbina/farmacocinética
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