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1.
Aquat Toxicol ; 228: 105629, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33002683

RESUMO

Hepatic in vitro biotransformation assays, in combination with in vitro-in vivo extrapolation (IVIVE) and bioaccumulation modeling, can be used to support regulatory bioaccumulation assessments. In most applications, however, these methods ignore the possibility of extrahepatic metabolism. Here we evaluated intestinal biotransformation in rainbow trout using S9 fractions prepared from the upper intestinal (GIT) epithelium. Measured levels of activity determined using standard substrates for phase I and phase II biotransformation enzymes were within 2-fold of activities measured in hepatic S9 fractions. In vitro intrinsic clearance rates for 2-ethylhexyl-4-methoxycinnamate (EHMC; an organic sunscreen agent) and two polycyclic aromatic hydrocarbons (pyrene [PYR] and benzo(a)pyrene [BAP]) were significantly higher in liver S9 fractions than in GIT S9 fractions. For octocrylene (OCT; a second sunscreen agent), however, in vitro intrinsic clearance rates were higher in GIT S9 fractions compared to liver S9 fractions. An existing 'liver only' IVIVE model was expanded to consider biotransformation in both the liver and GIT. Relevant IVIVE scaling factors were developed by morphological, histological, and biochemical evaluation of trout intestines. For chemicals biotransformed at higher rates by hepatic S9 fractions (i.e., BAP, PYR, EHMC), the 'liver & GIT' model yielded whole-body biotransformation rate constants (kMET) that were within 1.2 to 1.4-fold of those estimated using the 'liver only' model. In contrast to these findings, the mean kMET for OCT obtained using the 'liver & GIT' model was 3.3 times higher than the mean kMET derived using the 'liver only' model and was in good agreement with empirical kMET estimates determined previously for trout (<20 % difference). The results of this study suggest that current 'liver only' IVIVE approaches may underestimate in vivo biotransformation rates for chemicals that undergo substantial biotransformation in the GIT.


Assuntos
Trato Gastrointestinal/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Oncorhynchus mykiss/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Cinética , Taxa de Depuração Metabólica , Tamanho do Órgão , Poluentes Químicos da Água/toxicidade
2.
Aquat Toxicol ; 226: 105567, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32745893

RESUMO

The increasing contamination of water bodies with mercury (Hg) raises concerns about the possible effects of this metal on native fish species. Our current understanding of its dynamics in fish organs remains limited. In this study, adult individuals of the native species Astyanax eigenmanniorum were exposed to three environmentally relevant HgCl2 concentrations (5, 100, and 170 µg L-1) for 96 h. To evaluate total Hg (THg) elimination, new individuals were exposed to 100 µg L-1 of HgCl2 (96 h), and at the end of the exposure period, half of the fish were placed in tanks with clean water for 168 h. In both assays, the organs were removed, and THg levels were measured using ICP-MS. The uptake of IHg in A. eigenmanniorum showed a differential accumulation in the organs. Gills, intestine, and brain were the tissues with the highest THg levels. Finally, no elimination of THg in the water was observed, but intestine and gills significantly removed the THg accumulated. Probably a Hg redistribution through the tissues could take place.


Assuntos
Characidae/metabolismo , Mercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Adulto , Animais , Bioacumulação , Encéfalo/metabolismo , Characidae/sangue , Monitoramento Ambiental , Brânquias/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mercúrio/análise , Mercúrio/toxicidade , Taxa de Depuração Metabólica , Distribuição Tecidual , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
3.
Clin Pharmacokinet ; 59(10): 1251-1260, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32856282

RESUMO

BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Interleucina-6/sangue , Pneumonia Viral/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Betacoronavirus , Pesos e Medidas Corporais , Comorbidade , Citocromo P-450 CYP3A , Darunavir/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Pandemias , Estudos Retrospectivos , Fatores Sexuais
4.
Toxicol Lett ; 333: 4-12, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32736004

RESUMO

Nephrotoxicity is within the recognized toxic effects of arsenic. In this study we assessed the effect of arsenite on the renal capacity to metabolize and handle arsenicals in rats exposed to drinking water with 0, 1, 5, or 10 ppm sodium arsenite for ten days. Arsenite treatment did not affect the gene expression of the main enzyme catalyzing methylation of arsenite, As3mt, while it reduced the expression of GSTO1 mRNA and protein. Arsenite decreased the expression of Aqp3, Mrp1, Mrp4, and Mdr1b (i.e., transporters and channels used by arsenic), but not that of Aqp7, Glut1, Mrp2, and Mdr1a. The protein abundance of AQP3 was also reduced by arsenite. Arsenite increased urinary NGAL and FABP3 and decreased Klotho plasma levels, without alteration of creatinine, which evidenced early tubular damage. Renal Klotho mRNA and protein expressions were also downregulated, which may exacerbate renal damage. No effect was observed in selected miRNAs putatively associated with renal injury. Plasma PTH and FGF23 were similar between groups, but arsenite decreased the renal expression of Fgfr1 mRNA. In conclusion, exposure to arsenite alters the gene expression of proteins involved in the cellular handling of arsenical species and elicits tubular damage.


Assuntos
Arsenitos/toxicidade , Poluentes Ambientais/toxicidade , Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Compostos de Sódio/toxicidade , Animais , Arsenitos/sangue , Arsenitos/urina , Transporte Biológico , Relação Dose-Resposta a Droga , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Testes de Função Renal , Masculino , Taxa de Depuração Metabólica , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Compostos de Sódio/sangue , Compostos de Sódio/urina
8.
PLoS One ; 15(6): e0233925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530952

RESUMO

It is important to calculate the drug removal by hemodialysis (HD) for drug dosing regimens in HD patients. However, there are limited and inconsistent information about the dialyzability of drugs by HD. Therefore, the aim of our study is to evaluate drug removal by utilizing a rat model of HD (HD rat) and to extrapolate this result to the drug removal rate in HD patients. HD rats received bilateral nephrectomy and HD for 2 h. The dialysis removal of 6 drugs was evaluated in HD rats. Dialysis efficiency, plasma protein binding rate (PBR) and distribution volume (Vd) of drugs were also measured. Furthermore, we examined the correlation between the dialyzability of drug in HD rats and humans and constructed the prediction formula of the drug dialyzability in HD patients. The clearance of urea and creatinine and normalized dialysis dose in HD rats were 0.83 ± 0.07 mL/min, 0.70 ± 0.08 mL/min, and 0.13 ± 0.06, respectively. The drug dialyzability in HD rats was similar to reported clinical data except for doripenem. A higher correlation was observed between drug dialyzability in reported clinical data and HD rats which were adjusted for PBR (r2 = 0.936; p < 0.001) compared to unadjusted (r2 = 0.812; p = 0.009). Therefore, we constructed the prediction formula of the drug dialyzability in HD patients by utilizing the HD rat model and PBR. This study is useful for evaluating the dialyzability of high-risk drugs in a clinical setting and might provide appropriate preclinical dialyzability data for new drug.


Assuntos
Preparações Farmacêuticas/sangue , Diálise Renal/métodos , Eliminação Renal , Animais , Creatina/sangue , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Animais , Farmacocinética , Ratos , Ratos Wistar , Ureia/sangue
9.
Pharmacotherapy ; 40(8): 843-856, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32542785

RESUMO

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.


Assuntos
Azetidinas/farmacologia , Azetidinas/uso terapêutico , Infecções por Coronavirus/complicações , Inflamação/tratamento farmacológico , Inflamação/etiologia , Janus Quinases/antagonistas & inibidores , Pneumonia Viral/complicações , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Área Sob a Curva , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Interações Medicamentosas , Humanos , Interferon Tipo I/biossíntese , Taxa de Depuração Metabólica , Pandemias , Peptidil Dipeptidase A/biossíntese , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
10.
Toxicology ; 441: 152522, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32534104

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are organic chemicals with wide industrial and consumer uses. They are found ubiquitously at low levels in the environment and are detectable in humans and wildlife. Perfluorobutane Sulfonate (PFBS) is a short-chained PFAS used to replace perfluorooctane sulfonate in commerce. In general, the rate of clearance for the short-chained PFAS is faster than that for the long-chained congeners. This study evaluated the pharmacokinetic properties of PFBS and its hepatic transcriptional responses in CD-1 mice. Males and females were given PFBS by oral gavage at 30 or 300 mg/kg; controls received 0.5 % Tween-20 vehicle. Trunk blood was collected at 0.5, 1, 2, 4, 8, 16 and 24 h thereafter; liver and kidney were also harvested. Serum and tissue concentrations of PFBS were determined by HPLC-MS-MS. Expression of several hepatic nuclear receptor target genes was determined by qPCR. The half-life of PFBS was estimated as 5.8 h in the males and 4.5 h in the females. Tmax was reached within 1-2 h. Volume of distribution was similar between the two sexes (0.32-0.40 L/kg). The rate of PFBS clearance was linear with exposure doses. Within 24 h, serum PFBS declined to less than 5 % of Cmax. PFBS was detected in liver or kidney, although tissue levels of the chemical were only a fraction of those in serum. At 24 h after administration of 300 mg/kg PFBS, elevated expression of several hepatic genes targeted for PPARα, PPARy, and PXR but not by AhR, LXR or CAR was observed, with responses indistinguishable between males and females. Little to no transcriptional response was seen with the 30 mg/kg dose. The short serum half-lives of PFBS (4-5 h) in mice were comparable to those reported in rats. Although detection of PFBS in liver was low compared to that in serum even at the 300 mg/kg dose, the tissue level was sufficient to activate several hepatic nuclear receptors, which may represent an acute response to the chemical at a high dose.


Assuntos
Fluorcarbonetos/farmacocinética , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Ácidos Sulfônicos/farmacocinética , Animais , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Camundongos , Reação em Cadeia da Polimerase , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores Sexuais , Transcriptoma/efeitos dos fármacos
11.
Nutr Metab Cardiovasc Dis ; 30(8): 1272-1280, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32513580

RESUMO

BACKGROUND AND AIMS: Insulin clearance is a relevant process in glucose homeostasis. In this observational study, we aimed to assess insulin clearance (ClINS) in women with former gestational diabetes (fGDM) both early after delivery and after a follow-up. METHODS AND RESULTS: We analysed 59 fGDM women, and 16 women not developing GDM (CNT). All women underwent an oral glucose tolerance test (OGTT) yearly, and an insulin-modified intravenous glucose tolerance test (IVGTT) at baseline and at follow-up end (until 7 years). Both IVGTT and OGTT ClINS was assessed as insulin secretion to plasma insulin ratio. We also defined IVGTT first (0-10 min) and second phase (10-180 min) ClINS. We found that 14 fGDM women progressed to type 2 diabetes (PROG), whereas 45 women remained diabetes-free (NONPROG). At baseline, IVGTT ClINS showed alterations in PROG, especially in second phase (0.88 ± 0.10 l·min-1 in PROG, 0.60 ± 0.06 in NONPROG, 0.54 ± 0.07 in CNT, p ≤ 0.03). Differences in ClINS were not found from OGTT. Cox regression analysis showed second phase ClINS as significant type 2 diabetes predictor (hazard ratio = 1.90, 95% confidence interval 1.09-3.30, p = 0.02). CONCLUSION: This study showed that insulin clearance derived from an insulin-modified IVGTT is notably altered in women with history of GDM progressing towards type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Gestacional/sangue , Insulina/sangue , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/fisiopatologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Taxa de Depuração Metabólica , Modelos Biológicos , Gravidez , Fatores de Risco , Fatores de Tempo
12.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188382, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32522600

RESUMO

Liver cancer is highly malignant and insensitive to cytotoxic chemotherapy and is associated with very poor patient prognosis. In 2007, the small-molecule targeted drug sorafenib was approved for the treatment of advanced liver cancer. In the subsequent ten years, sorafenib has been the only first-line therapeutic targeted drug for advanced hepatocellular carcinoma (HCC). However, a number of clinical studies show that a considerable percentage of patients with liver cancer are insensitive to sorafenib. The number of patients who actually benefit significantly from sorafenib treatment is very limited, and the overall efficacy of sorafenib is far from satisfactory, which has attracted the attention of researchers. Based on previous studies and reports, this article reviews the potential mechanisms of sorafenib resistance (SR) and summarizes the biomarkers and clinicopathological indicators that might be used for predicting sorafenib response and developing personalized therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hepáticas/tratamento farmacológico , Medicina de Precisão , Sorafenibe/farmacologia , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/economia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Análise Custo-Benefício , Progressão da Doença , Humanos , Fígado/patologia , Neoplasias Hepáticas/economia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Taxa de Depuração Metabólica/genética , Estadiamento de Neoplasias , Seleção de Pacientes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/economia , Sorafenibe/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
13.
Clin Pharmacol Ther ; 108(5): 976-984, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32531808

RESUMO

We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZ) in the lungs is sensitive to changes in lung pH, a parameter that can be affected in patients with coronavirus disease 2019 (COVID-19). A reduction in pH from 6.7 to 6 in the lungs, as observed in respiratory disease, led to 20-fold, 4.0-fold, and 2.7-fold increases in lung exposure of CQ, HCQ, and AZ, respectively. Simulations indicated that the relatively high concentrations of CQ and HCQ in lung tissue were sustained long after administration of the drugs had stopped. Patients with COVID-19 often present with kidney failure. Our simulations indicate that renal impairment (plus lung pH reduction) caused 30-fold, 8.0-fold, and 3.4-fold increases in lung exposures for CQ, HCQ, and AZ, respectively, with relatively small accompanying increases (20 to 30%) in systemic exposure. Although a number of different dosage regimens were assessed, the purpose of our study was not to provide recommendations for a dosing strategy, but to demonstrate the utility of a physiologically-based pharmacokinetic modeling approach to estimate lung concentrations. This, used in conjunction with robust in vitro and clinical data, can help in the assessment of COVID-19 therapeutics going forward.


Assuntos
Azitromicina/farmacocinética , Infecções por Coronavirus , Hidroxicloroquina/farmacocinética , Pulmão , Pandemias , Pneumonia Viral , Anti-Infecciosos/farmacocinética , Antivirais/farmacocinética , Betacoronavirus/fisiologia , Disponibilidade Biológica , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Taxa de Depuração Metabólica , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia
15.
Pharm Res ; 37(6): 95, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32405699

RESUMO

During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective.


Assuntos
Modelos Biológicos , Modelos Químicos , Preparações Farmacêuticas/química , Administração Oral , Animais , Humanos , Absorção Intestinal , Taxa de Depuração Metabólica , Permeabilidade , Farmacocinética , Solubilidade , Tecnologia Farmacêutica , Distribuição Tecidual
16.
Pharm Res ; 37(6): 96, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409892

RESUMO

PURPOSE: Clearance via renal replacement therapy (RRT) can significantly alter the pharmacokinetic profile of drugs. The aim of this study was (i) to improve the use of clinical trial data and (ii) to provide a model that allows quantification of all aspects of drug elimination via RRT including adsorption to dialysis membranes and/or degradation of the drug in the dialysate. METHODS: An integrated dialysis pharmacometric (IDP) model was developed to simultaneously incorporate all available RRT information. The sensitivity, accuracy and precision of the IDP model was compared to conventional approaches in clinical trial simulations and applied to clinical datasets of teicoplanin and doripenem. RESULTS: The IDP model was more accurate, precise and sensitive than conventional plasma-concentration-based approaches when estimating the clearanceRRT (relative bias <1%). In contrast to conventional approaches, adsorption and degradation were quantifiable using the IDP model (relative bias: -1.1% and - 1.9%, respectively). Applied to clinical data, clearanceRRT, drug degradation (effluent-half-lifedoripenem: 13.5 h-1) and adsorption (polysulphone adsorption capacityteicoplanin: 31.2 mg) were assessed. CONCLUSION: The IDP model allows accurate, precise and sensitive characterization of clearanceRRT, adsorption and degradation. Successful quantification of all aspects of clearanceRRT in clinical data demonstrated the benefit of the IDP model as compared to conventional approaches.


Assuntos
Lesão Renal Aguda/terapia , Antibacterianos/farmacologia , Doripenem/farmacologia , Modelos Biológicos , Teicoplanina/farmacocinética , Adsorção , Simulação por Computador , Sistemas de Gerenciamento de Base de Dados , Estabilidade de Medicamentos , Humanos , Taxa de Depuração Metabólica , Estudos Prospectivos , Diálise Renal/métodos , Terapia de Substituição Renal , Medição de Risco
17.
PLoS One ; 15(5): e0233010, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396581

RESUMO

Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11ß-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.


Assuntos
Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metanfetamina/administração & dosagem , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/toxicidade , Citocromo P-450 CYP1A2/genética , Feminino , Cobaias , Humanos , Taxa de Depuração Metabólica , Redes e Vias Metabólicas/efeitos dos fármacos , Metanfetamina/sangue , Metanfetamina/toxicidade , Modelos Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Toxicol Appl Pharmacol ; 400: 115069, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32445755

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease in the Western countries with increasing prevalence worldwide, may substantially affect chemical toxicokinetics and thereby modulate chemical toxicity. OBJECTIVES: This study aims to use physiologically-based pharmacokinetic (PBPK) modeling to characterize the impact of NAFLD on toxicokinetics of perchloroethylene (perc). METHODS: Quantitative measures of physiological and biochemical changes associated with the presence of NAFLD induced by high-fat or methionine/choline-deficient diets in C57B1/6 J mice are incorporated into a previously developed PBPK model for perc and its oxidative and conjugative metabolites. Impacts on liver fat and volume, as well as blood:air and liver:air partition coefficients, are incorporated into the model. Hierarchical Bayesian population analysis using Markov chain Monte Carlo simulation is conducted to characterize uncertainty, as well as disease-induced variability in toxicokinetics. RESULTS: NAFLD has a major effect on toxicokinetics of perc, with greater oxidative and lower conjugative metabolism as compared to healthy mice. The NAFLD-updated PBPK model accurately predicts in vivo metabolism of perc through oxidative and conjugative pathways in all tissues across disease states and strains, but underestimated parent compound concentrations in blood and liver of NAFLD mice. CONCLUSIONS: We demonstrate the application of PBPK modeling to predict the effects of pre-existing disease conditions as a variability factor in perc metabolism. These results suggest that non-genetic factors such as diet and pre-existing disease can be as influential as genetic factors in altering toxicokinetics of perc, and thus are likely contribute substantially to population variation in its adverse effects.


Assuntos
Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tetracloroetileno/toxicidade , Animais , Teorema de Bayes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Tetracloroetileno/sangue , Tetracloroetileno/farmacocinética , Toxicocinética
19.
Xenobiotica ; 50(10): 1208-1219, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32352885

RESUMO

Liver enzymes and transporters play an essential role in xenobiotic metabolism, distribution and elimination. Pre-clinical safety assessment relies on studies on animal models, including the (mini)pig. The pig shares many anatomical and physiological characteristics with humans, and there is currently a gap in information about porcine metabolism and disposition pathways and their similarities and differences from human ones.Three different sample preparation methods (filter-aided sample preparation (FASP), enhanced FASP (eFASP) and in-solution sample preparation) were used to prepare porcine liver tissue (two samples) for proteomic analysis. The analysis relied on rapid-separation liquid chromatography coupled to Orbitrap mass spectrometry in data-dependent acquisition mode. MASCOT was used for identification and relative label-free quantification was based on spectral counting.The three sample preparation methods provided complementary results, allowing characterisation of approximately 70 pharmacologically relevant proteins. The main quantified proteins included 16 cytochrome P450 (CYP) enzymes, 5 UGT enzymes, and 11 transporters. In addition, 20 Phase I and 14 Phase II enzymes were also characterised. Inter-operator differences were negligible and the pig liver pies for CYP, UGT and efflux transporter proteins were established. Human homologues of the quantified CYP, UGT and transporter proteins were identified.


Assuntos
Transporte Biológico/fisiologia , Inativação Metabólica/fisiologia , Taxa de Depuração Metabólica/fisiologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado , Proteômica , Suínos
20.
Clin Nephrol ; 94(1): 43-49, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32383639

RESUMO

The purpose of this NephEd contribution is to introduce a generic method for analyzing plasma concentrations ([x]p). The method is applicable to substances that are filtered by glomeruli, reabsorbed or secreted by tubules, and excreted in urine. The equality from which the method follows states that the filtration rate of substance x is the sum of excretion and net reabsorption rates of x (Fx = Ex + TRx). If x is completely ultrafilterable, Fx = GFR[x]p, and [x]p = Ex/GFR + TRx/GFR. If creatinine clearance (Ccr) is substituted for GFR, Ex/Ccr simplifies to [x]u[cr]p/[cr]u, which can be calculated from measurements in simultaneous aliquots of serum and urine. TRx/Ccr is then deduced as [x]p - Ex/Ccr. The ratios Ex/Ccr and TRx/Ccr - the determinants of [x]p - quantify the amounts of x excreted and reabsorbed per volume of filtrate. If [x]p is abnormal, the generic method identifies which of the determinants is creating the abnormality. If [x]p is normal despite disruptive circumstances, e.g., a reduced GFR, the method elucidates the preservation of normalcy. Herein, we develop these concepts and illustrate their practical utility.


Assuntos
Biomarcadores/sangue , Taxa de Filtração Glomerular/fisiologia , Testes de Função Renal/métodos , Glomérulos Renais/fisiologia , Biomarcadores/metabolismo , Biomarcadores/urina , Creatinina/sangue , Creatinina/metabolismo , Creatinina/urina , Humanos , Taxa de Depuração Metabólica/fisiologia
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