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1.
Yakugaku Zasshi ; 140(1): 81-90, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902889

RESUMO

We previously reported the association of the estimated glomerular filtration rate (eGFRcreat) calculated from the serum creatinine level (S-Cr) measured using the Jaffe method with the GFR (eGFRcys) estimated from the serum cystatin C level (CysC). However, few studies have compared the eGFRcreat using the enzymatic method with the eGFRcys. It is unclear whether there are differences in the results of renal function assessment. The purpose of this study was to compare the eGFRcreat calculated from the S-Cr with the eGFRcys calculated from the CysC in patients in whom the S-Cr and CysC were simultaneously measured using the enzymatic method, examine the correlations of respective parameters, and clarify physiological factors involved in differences among the parameters. The subjects were 1334 patients treated in 5 institutions. The mean values and correlation coefficient were statistically analyzed using Student's t-test and Pearson's test, respectively. Influential factors between formulae were analyzed using multiple regression analysis. The mean eGFRcreat was 67.0 mL/min/1.73 m2, being significantly higher than the mean eGFRcys (63.2). Multiple regression analysis showed that factors influencing differences in the S-Cr and CysC included the sex, age, serum albumin, and blood urea nitrogen BUN/S-Cr. Furthermore, factors involved in the overestimation of the eGFRcreat in comparison with the eGFRcys included the serum albumin and BUN/S-Cr. The differences between the eGFRcreat calculated from the S-Cr and eGFRcys were less marked than when adopting the Jaffe method in our previous study. However, the eGFRcreat were higher than the eGFRcys in patients with malnutrition or dehydration.


Assuntos
Creatinina/sangue , Cistatina C/sangue , Ensaios Enzimáticos/métodos , Testes de Função Renal/métodos , Insuficiência Renal Crônica/diagnóstico , Biomarcadores/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Taxa de Depuração Metabólica
2.
Xenobiotica ; 50(1): 92-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31601149

RESUMO

The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites.This review identifies carboxylesterase substrates and describes our current understanding of the influence of genetic polymorphisms on substrate disposition and clinical effects. Several polymorphisms are described in the literature and included in the personalized medicine database PharmGKB, but there are no carboxylesterase genotypes referenced in Food and Drug Administration approved drug labeling. The limited validation of metabolic pathways for drugs undergoing hydrolysis, and the small number of studies evaluating genotype-drug interactions confirm that this is an emerging field of drug metabolism research.The dependence of prodrugs, many with low therapeutic indexes, on carboxylesterase-mediated hydrolysis indicate that genetic variation plays an important role in prodrug activation, and that carboxylesterase genotyping will become an important component of personalized medicine.


Assuntos
Hidrolases de Éster Carboxílico/genética , Medicina de Precisão , Hidrolases de Éster Carboxílico/metabolismo , Interações de Medicamentos , Genótipo , Humanos , Hidrólise , Inativação Metabólica/genética , Taxa de Depuração Metabólica , Polimorfismo Genético , Pró-Fármacos , Especificidade por Substrato
3.
Xenobiotica ; 50(1): 3-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524553

RESUMO

The events leading up to the discovery of genetically controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field.The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.


Assuntos
Taxa de Depuração Metabólica , Farmacogenética , Inativação Metabólica , Xenobióticos/metabolismo
4.
Toxicol Lett ; 320: 46-51, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812603

RESUMO

Pterostilbene (PT) is a natural stilbene common in small berries and food supplements, possessing numerous pharmacological activities. However, whether PT can affect the activities of UDP-glucuronosyltransferases (UGT) enzymes remains unclear. The aim of the present study was to investigate the effect of PT on UGT activities and to quantitatively evaluate the food-drug interaction potential due to UGT inhibition. Our data indicated that PT exhibited potent inhibition against HLM, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, moderate inhibition against UGT1A1, UGT1A3, UGT1A8, and UGT2B4, negligible inhibition against UGT1A4, UGT1A7, UGT1A10, and UGT2B17. Further kinetic investigation demonstrated that PT exerted potent noncompetitive inhibition 4-MU glucuronidation by UGT1A9, with IC50 and Ki values of 0.92 µM and 0.52 ± 0.04 µM, respectively. Quantitative prediction study suggested that coadministration of PT supplements at 100 mg/day or higher doses may result in at least a 50% increase in the AUC of drugs predominantly cleared by UGT1A9. Thus, the coadministration of PT supplements and drugs primarily cleared by UGT1A9 may result in potential drug interaction, and precautions should be taken when coadministration of PT supplements and drugs metabolized by UGT1A9.


Assuntos
Suplementos Nutricionais/efeitos adversos , Inibidores Enzimáticos/toxicidade , Interações Alimento-Droga , Glucuronosiltransferase/antagonistas & inibidores , Estilbenos/toxicidade , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Taxa de Depuração Metabólica , Desintoxicação Metabólica Fase II , Modelos Biológicos , Medição de Risco , Estilbenos/farmacocinética
5.
Toxicol Lett ; 321: 95-102, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31816331

RESUMO

Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107-164 µg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10-40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17-0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03-0.10%) and 0.05% (0.01-0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5-2.3 h, tmax2 = 3.8-6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1-3.8 h. The majority (98-100%) of metabolites was excreted within 24 h. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 µg/kg bw/day). The highest daily intake (114 µg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.


Assuntos
Adipatos/administração & dosagem , Adipatos/urina , Plastificantes/administração & dosagem , Eliminação Renal , Adipatos/efeitos adversos , Adipatos/farmacocinética , Administração Oral , Adulto , Biotransformação , Feminino , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Plastificantes/efeitos adversos , Plastificantes/farmacocinética , Medição de Risco , Adulto Jovem
6.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações de Medicamentos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
7.
Pharm Res ; 36(12): 171, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654287

RESUMO

PURPOSE: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. METHODS: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. RESULTS: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. CONCLUSIONS: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.


Assuntos
Analgésicos Opioides/farmacocinética , Oxicodona/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Criança , Pré-Escolar , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Lactente , Recém-Nascido , Taxa de Depuração Metabólica , Modelos Biológicos , Oxicodona/administração & dosagem , Pediatria
8.
BMC Res Notes ; 12(1): 655, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604451

RESUMO

OBJECTIVES: This study validates two popular predictive equations of renal function firstly, Modifications of Diet in Renal Disease and secondly, Chronic Kidney Disease Epidemiology Collaboration equations for Sri Lankan cohort. We used data of the patients referred to Renal Research lab of University of Colombo for creatinine clearance measurement. RESULTS: Predictive performances varied with the gender. Creatinine clearance and predicted renal functions were compared. Both fared unsatisfactorily with R2 ranging from 0.632 to 0.652, and overestimated renal function by 6-15%. The proportion chronic kidney disease staging 1 and 2 returned by Chronic Kidney Disease Epidemiology Collaboration equation showed significant difference, in females. Modifications of Diet in Renal Disease equation significantly under-estimated advanced chronic kidney disease in females. Chronic Kidney Disease Epidemiology Collaboration equation had better accuracy. The study sample had more females, Asian and lower body size and better renal functions than historic cohorts. Thai and Pakistani studies show both equations and their Asian adaptations fare poorly. Chronic kidney disease stages differ significantly with the equation used. Predictive equations have fared unsatisfactorily by overestimating renal functions. We recommend further studies using gold standards of measuring renal function.


Assuntos
Creatinina/farmacocinética , Nefropatias/fisiopatologia , Testes de Função Renal/métodos , Insuficiência Renal Crônica/fisiopatologia , Adulto , Algoritmos , Estudos de Coortes , Dieta , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Teóricos , Valor Preditivo dos Testes , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismo , Sri Lanka
9.
Bull Environ Contam Toxicol ; 103(5): 729-733, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31531704

RESUMO

Accumulation of nonylphenol (NP) in hepatopancreas, gonad, eyestalk, and muscle of freshwater prawn Macrobrachium rosenbergii following 72 h exposure to 100 µg/L NP, and depuration of NP in these tissues at 0.5-192 h post exposure were examined. We also examined the expressions of vitellogenin (Vg) and vitellogenin receptor (VgR) of prawn following 0-20 days exposure to 0, 1, 10, and 100 µg/L NP. NP accumulation in hepatopancreas and gonad with high concentration, and low concentration in muscle, but depurated faster in eyestalk and muscle. The expressions of vitellogenin (Vg) and vitellogenin receptor (VgR) increased directly with dose and time. In conclusion, NP accumulated significantly in gonad together with high Vg and VgR expressions, and depurated slow in hepatopancreas and gonad when prawns were removed back to control water. The induction of Vg and VgR under NP exposure might be a stress response in M. rosenbergii.


Assuntos
Proteínas do Ovo/genética , Água Doce/química , Palaemonidae/efeitos dos fármacos , Fenóis/toxicidade , Receptores de Superfície Celular/genética , Vitelogeninas/genética , Poluentes Químicos da Água/toxicidade , Animais , Bioacumulação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Taxa de Depuração Metabólica , Palaemonidae/metabolismo , Fenóis/metabolismo , Poluentes Químicos da Água/metabolismo
10.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540101

RESUMO

Sesquiterpenes, the main components of plant essential oils, are bioactive compounds with numerous health-beneficial activities. Sesquiterpenes can interact with concomitantly administered drugs due to the modulation of drug-metabolizing enzymes (DMEs). The aim of this study was to evaluate the modulatory effects of six sesquiterpenes (farnesol, cis-nerolidol, trans-nerolidol, α-humulene, ß-caryophyllene, and caryophyllene oxide) on the expression of four phase I DMEs (cytochrome P450 3A4 and 2C, carbonyl reductase 1, and aldo-keto reductase 1C) at both the mRNA and protein levels. For this purpose, human precision-cut liver slices (PCLS) prepared from 10 patients and transfected HepG2 cells were used. Western blotting, quantitative real-time PCR and reporter gene assays were employed in the analyses. In the reporter gene assays, all sesquiterpenes significantly induced cytochrome P450 3A4 expression via pregnane X receptor interaction. However in PCLS, their effects on the expression of all the tested DMEs at the mRNA and protein levels were mild or none. High inter-individual variabilities in the basal levels as well as in modulatory efficacy of the tested sesquiterpenes were observed, indicating a high probability of marked differences in the effects of these compounds among the general population. Nevertheless, it seems unlikely that the studied sesquiterpenes would remarkably influence the bioavailability and efficacy of concomitantly administered drugs.


Assuntos
Aldo-Ceto Redutases/metabolismo , Carbonil Redutase (NADPH)/metabolismo , Citocromo P-450 CYP3A/metabolismo , Família 2 do Citocromo P450/metabolismo , Receptor de Pregnano X/agonistas , Sesquiterpenos/farmacologia , Idoso , Idoso de 80 Anos ou mais , Sistema Enzimático do Citocromo P-450/metabolismo , Farneseno Álcool/farmacologia , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Fígado/enzimologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , /farmacologia , Receptor de Pregnano X/metabolismo , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo
11.
Arch Dis Child Fetal Neonatal Ed ; 104(6): F598-F603, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31498775

RESUMO

BACKGROUND: Fentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation. METHODS: 442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9-31.9) weeks, postnatal age: 3 (range 0-68) days, bodyweight 1.00 (range 0.39-2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations. RESULTS: Fentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0-4 days and 5-9 days in comparison to 10 days and older. CONCLUSION: Because of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.


Assuntos
Peso ao Nascer/fisiologia , Fentanila/farmacocinética , Recém-Nascido Prematuro/fisiologia , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro/fisiologia , Recém-Nascido , Masculino , Taxa de Depuração Metabólica , Estudos Prospectivos
12.
Biol Pharm Bull ; 42(9): 1590-1595, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474719

RESUMO

There are large inter- and intra-individual variations in CYP3A4 activity. Midazolam, which is predominantly metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam by CYP3A4, is considered an effective probe for CYP3A4. To determine the area under the curve (AUC) of midazolam or midazolam clearance for CYP3A4 activity, multiple plasma samples of midazolam are required. This study aimed to evaluate whether measurement of a single plasma concentration or urinary excretion of midazolam could be used to predict the AUC of midazolam in healthy volunteers. We conducted a retrospective analysis of two pharmacokinetic studies. Nineteen volunteers received intravenous (5, 15, and 30 µg/kg) and oral (15, 50, and 100 µg/kg) administration of midazolam on sequential days. The midazolam concentration in plasma and urine was determined by LC-MS/MS. Plasma midazolam concentrations showed a good correlation with the AUC at all blood sampling points after the administrations. The coefficient of determination was highest at 1-2 and 2-4 h after intravenous (>0.96) and oral administration (>0.94), respectively, among all the sampling times. The errors for bias and accuracy of prediction were the lowest at 1.5 and 4 h after intravenous and oral administration, respectively. In case of urinary excretion, a significant positive correlation between midazolam and the AUC was observed only after oral administration. Thus, the AUC of midazolam can be evaluated by blood sampling at 1.5 h after intravenous administration and at 4 h after oral administration.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Voluntários Saudáveis , Midazolam/administração & dosagem , Midazolam/sangue , Midazolam/urina , Administração Oral , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Taxa de Depuração Metabólica , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo
13.
Am J Health Syst Pharm ; 76(19): 1472-1480, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532503

RESUMO

PURPOSE: The changes in physiological functions as children grow and organ systems mature result in pharmacokinetic alterations throughout childhood. These alterations in children result in absorption, distribution, metabolism, and excretion of drugs that are different from those seen in the typical adult diseased population. SUMMARY: Changes in gastrointestinal motility and gastric pH in neonates and infants affect the absorption rate and bioavailability of drugs. Skin absorption rate and extent can be altered by different skin structures and perfusion in young children. Intramuscular and rectal absorption become less predictable in children due to erratic absorption site perfusion and other factors. Children's body compositions also differ greatly from that in adults. Water-soluble drugs distribute more extensively in newborns due to larger water content than in older children and adults. Drug elimination and excretion are also affected in pediatric population due to differences in liver and renal function. Immature enzyme development and renal function result in reduced clearance of drugs in young children. There are limited pharmacokinetic data available for many drugs used in children. CONCLUSION: Considering the changes in pharmacokinetics in children can help pharmacists optimize the dosing and monitoring of drugs and do the best they can to help this vulnerable population.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Desenvolvimento Infantil/fisiologia , Conduta do Tratamento Medicamentoso , Taxa de Depuração Metabólica/fisiologia , Farmacocinética , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Absorção Gastrointestinal/fisiologia , Motilidade Gastrointestinal/fisiologia , Humanos , Lactente , Recém-Nascido , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Farmacêuticos , Absorção Cutânea/fisiologia
14.
Bull Environ Contam Toxicol ; 103(5): 657-662, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31492971

RESUMO

This study evaluated the dependence of mercury (Hg) elimination by fish on species specific fish metabolic rate in order to generate improved algorithms of Hg elimination rate coefficients. Mercury elimination rate coefficient observations were collected by literature review and fish routine metabolic rate (RMR) estimates calculated using the Wisconsin Fish Bioenergetics Model. Three models were compared that considered body weight, temperature, thermal category, Hg depuration period and RMR as predictors of Hg elimination. The best performing model incorporated body size, temperature and fish thermal category, explaining 79% of the variation of the calibration data and between 20% and 69% of the variation of validation data sets. The results support the conclusion that species-specific differences in metabolic rate influence mercury elimination by fish but also highlight major data gaps in the mercury toxicokinetic literature necessary to develop robust models Hg elimination by fish.


Assuntos
Monitoramento Ambiental/métodos , Peixes/metabolismo , Mercúrio/metabolismo , Modelos Biológicos , Poluentes Químicos da Água/metabolismo , Animais , Temperatura Corporal , Mercúrio/análise , Taxa de Depuração Metabólica , Alimentos Marinhos , Especificidade da Espécie , Poluentes Químicos da Água/análise , Wisconsin
15.
J Toxicol Sci ; 44(8): 543-548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31378765

RESUMO

Long-term exposure to certain volatile organic compounds is a significant public health concern. A variety of food containers and drinking cups prepared from polystyrene or polystyrene-related plastics could contain styrene monomer. In the current study, the concentrations of styrene in plasma and liver were surveyed and determined after oral doses of 25 mg/kg to rats and 200 mg/kg to control and humanized-liver mice. Plasma concentrations of styrene in rats were still detected 2 hr after 10-25 mg/kg oral doses. In contrast, after an order of magnitude higher oral dose of styrene (200 mg/kg) to mice, styrene in mouse plasma was rapidly cleared within 15 min to the limit-of-detection level. However, unmetabolized styrene was detected in mouse liver 24 hr after oral treatment. A simple physiologically based pharmacokinetic (PBPK) model capable of estimating blood and liver concentrations of styrene was established for rats. A human PBPK model was then set up for styrene by using the same intrinsic hepatic clearances in rats and humans and by applying allometric scaling to rat parameters obtained from the plasma concentrations of styrene in rats. By reverse dosimetry analysis (from concentrations to doses), we found that the 95th percentile values of styrene concentrations (0.132 ng/mL) reported in United States biomonitoring data of more than 1000 human blood samples may imply exposure to repeated oral doses of styrene of 2.89 µg/kg/day. These results suggest that styrene biomonitoring data in human blood samples imply exposures roughly similar to or lower than the established tolerable daily intake level of 7.7 µg/kg/day.


Assuntos
Fígado/metabolismo , Estireno/sangue , Estireno/farmacocinética , Administração Oral , Animais , Embalagem de Alimentos , Masculino , Taxa de Depuração Metabólica , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Modelos Animais , Modelos Biológicos , Nível de Efeito Adverso não Observado , Ratos Sprague-Dawley , Estireno/administração & dosagem , Fatores de Tempo
16.
Eur J Pharm Biopharm ; 143: 18-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419586

RESUMO

Retinal pigment epithelium (RPE) is a major part of blood-retinal barrier that affects drug elimination from the vitreous to the blood and drug distribution from blood circulation into the eye. Even though drug clearance from the vitreous has been well studied, the role of RPE in the process has not been quantified. The aim of this work was to study the role of RPE clearance (CLRPE) as part of drug elimination from the vitreous and ocular drug distribution from the systemic blood circulation. We determined the bidirectional permeability of eight small molecular weight drugs and bevacizumab antibody across isolated bovine RPE-choroid. Permeability of small molecules was 10-6-10-5 cm/s showing 13-15 fold range of outward and inward permeation, while permeability of bevacizumab was lower by 2-3 orders of magnitude. Most small molecular weight drugs showed comparable outward (vitreous-to-choroid) and inward (choroid-to-vitreous) permeability across the RPE-choroid, except ciprofloxacin and ketorolac that had an over 6 and 14-fold higher outward than inward permeability, respectively, possibly indicating active transport. Six of seven tested small molecular weight drugs had outward CLRPE values that were comparable with their intravitreal clearance (CLIVT) values (0.84-2.6 fold difference). On the contrary, bevacizumab had an outward CLRPE that was only 3.5% of the CLIVT, proving that its main route of elimination (after intravitreal injection) is not RPE permeation. Experimental values were used in pharmacokinetic simulations to assess the role of the RPE in drug transfer from the systemic blood circulation to the vitreous (CLBV). We conclude that for small molecular weight drugs the RPE is an important route in drug transfer between the vitreal cavity and blood, whereas it effectively hinders the movement of bevacizumab from the vitreous to the systemic circulation.


Assuntos
Preparações Farmacêuticas/metabolismo , Segmento Posterior do Olho/metabolismo , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Animais , Transporte Biológico/fisiologia , Transporte Biológico Ativo/fisiologia , Barreira Hematorretiniana/metabolismo , Bovinos , Corioide/metabolismo , Injeções Intravítreas , Taxa de Depuração Metabólica/fisiologia , Permeabilidade
17.
Pharm Biol ; 57(1): 550-554, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31429612

RESUMO

Context: Paeoniflorin is reported to possess numerous pharmacological activities. Paeoniflorin and glycyrrhizin are always used together for the treatment of disease in China clinics; however, the drug-drug interaction between glycyrrhizin and paeoniflorin is still unknown. Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of paeoniflorin in rats. Materials and methods: The pharmacokinetics of orally administered paeoniflorin (20 mg/kg) with or without glycyrrhizin pre-treatment (at a dose of 100 mg/kg/day for 7 days) were investigated in male Sprague-Dawley rats using LC-MS/MS. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. Results: The results showed that when the rats were pre-treated with glycyrrhizin, the Cmax of paeoniflorin decreased from 59.57 ± 10.24 to 45.36 ± 8.61 ng/mL, and AUC0-inf also decreased from 282.02 ± 35.06 to 202.29 ± 28.28 µg·h/L. The t1/2 value of paeoniflorin decreased from 8.48 ± 2.01 to 5.88 ± 1.15 h (p < 0.05). The Caco-2 cell transwell experiments indicated that glycyrrhizin could increase the efflux ratio of paeoniflorin from 2.71 to 3.52, and the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase its intrinsic clearance rate from 53.7 ± 4.6 to 85.6 ± 7.1 µL/min/mg protein. Conclusions: These results indicated that glycyrrhizin could affect the pharmacokinetics of paeoniflorin, and it might work through decreasing the absorption of paeoniflorin by inducing the activity of P-gp or through increasing the clearance rate in rat liver by inducing the activity of CYP450 enzyme.


Assuntos
Glucosídeos/farmacocinética , Ácido Glicirrízico/farmacologia , Microssomos Hepáticos/metabolismo , Monoterpenos/farmacocinética , Animais , Transporte Biológico , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos , Glucosídeos/sangue , Humanos , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Monoterpenos/sangue , Permeabilidade , Ratos Sprague-Dawley
18.
Environ Sci Technol ; 53(18): 10601-10611, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31412202

RESUMO

In this paper we describe the identification of two classes of contaminants: sulfonated-PCBs and hydroxy-sulfonated-PCBs. This is the first published report of the detection of these chemicals in soil. They were found, along with hydroxy-PCBs, in soil samples coming from a site historically contaminated by the industrial production of PCBs and in background soils. Sulfonated-PCB levels were approximately 0.4-0.8% of the native PCB levels in soils and about twice the levels of hydroxy-sulfonated-PCBs and hydroxy-PCBs. The identification of sulfonated-PCBs was confirmed by the chemical synthesis of reference standards, obtained through the sulfonation of an industrial mixture of PCBs. We then reviewed the literature to investigate for the potential agents responsible for the sulfonation. Furthermore, we predicted their physicochemical properties and indicate that, given the low pKa of sulfonated- and hydroxy-sulfonated-PCBs, they possess negligible volatility, supporting the case for in situ formation from PCBs. This study shows the need of understanding their origin, their role in the degradation path of PCBs, and their fate, as well as their (still unknown) toxicological and ecotoxicological properties.


Assuntos
Bifenilos Policlorados , Poluentes do Solo , Alcanossulfonatos , Taxa de Depuração Metabólica , Solo
19.
Ecotoxicol Environ Saf ; 183: 109527, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31400723

RESUMO

Eutrophication is an ecological process that results in cyanobacterial blooms. Microcystin-LR is the most toxic variant of microcystins and may cause toxic effects in the organisms, mainly in hepatic tissues. The aims of this study were to use multiple biomarkers in order to evaluate the sublethal effects of a low concentration of MC-LR (1 µg/L) in fish Geophagus brasiliensis by waterborne exposure; and evaluate the depuration of this toxin during 15 days. A group of 30 fish was exposed to 1 µg/L of MC-LR solution for 96 h in a static bioassay. After this time, blood, brain, muscle, liver, gonad and gills were collected from half of the exposed fish group in order to evaluate chemical, biochemical, histological and genotoxic biomarkers. The rest of the fish group was submitted to the depuration experiment with free MC-LR water for 15 days. After this time the same tissues were collected and evaluated using biomarkers analysis. Toxic effects were found mostly in the fish liver from depuration time as alterations on the antioxidant system and histopathologies. The results showed that even low concentrations can cause sublethal effects to aquatic organisms, and cyanotoxins monitoring and regulation tools are required.


Assuntos
Ciclídeos/metabolismo , Microcistinas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Ciclídeos/sangue , Ciclídeos/genética , Relação Dose-Resposta a Droga , Eutrofização , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Taxa de Depuração Metabólica , Microcistinas/metabolismo , Especificidade de Órgãos , Alimentos Marinhos , Poluentes Químicos da Água/metabolismo
20.
Part Fibre Toxicol ; 16(1): 29, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288843

RESUMO

BACKGROUND: Industrially produced quantities of TiO2 nanoparticles are steadily rising, leading to an increasing risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure. RESULTS: To study the fate of inhaled TiO2-NP, adult rats were exposed to 2-h intra-tracheal inhalations of 48V-radiolabeled, 20 nm TiO2-NP aerosols (deposited NP-mass 1.4 ± 0.5 µg). At five time points (1 h, 4 h, 24 h, 7d, 28d) post-exposure, a complete balance of the [48V]TiO2-NP fate was quantified in organs, tissues, carcass, lavage and body fluids, including excretions. After fast mucociliary airway clearance (fractional range 0.16-0.31), long-term macrophage-mediated clearance (LT-MC) from the alveolar region is 2.6-fold higher after 28d (integral fraction 0.40 ± 0.04) than translocation across the air-blood-barrier (integral fraction 0.15 ± 0.01). A high NP fraction remains in the alveoli (0.44 ± 0.05 after 28d), half of these on the alveolar epithelium and half in interstitial spaces. There is clearance from both retention sites at fractional rates (0.02-0.03 d- 1) by LT-MC. Prior to LT-MC, [48V]TiO2-NP are re-entrained to the epithelium as reported earlier for 20 nm inhaled gold-NP (AuNP) and iridium-NP (IrNP). CONCLUSION: Comparing the 28-day biokinetics patterns of three different inhaled NP materials TiO2-NP, AuNP and IrNP, the long-term kinetics of interstitial relocation and subsequent re-entrainment onto the lung-epithelium is similar for AuNP and Ir-NP but slower than for TiO2-NP. We discuss mechanisms and pathways of NP relocation and re-entrainment versus translocation. Additionally, after 28 days the integral translocated fractions of TiO2-NP and IrNP across the air-blood-barrier (ABB) are similar and become 0.15 while the translocated AuNP fraction is only 0.04. While NP dissolution proved negligible, translocated TiO2-NP and IrNP are predominantly excreted in urine (~ 0.1) while the urinary AuNP excretion amounts to a fraction of only 0.01. Urinary AuNP excretion is below 0.0001 during the first week but rises tenfold thereafter suggesting delayed disagglomeration. Of note, all three NP dissolve minimally, since no ionic radio-label release was detectable. These biokinetics data of inhaled, same-sized NP suggest significant time-dependent differences of the ABB translocation and subsequent fate in the organism.


Assuntos
Exposição por Inalação/análise , Pulmão/metabolismo , Nanopartículas/química , Titânio/farmacocinética , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar , Feminino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Tamanho da Partícula , Ratos , Ratos Endogâmicos WKY , Mucosa Respiratória/metabolismo , Fatores de Tempo , Distribuição Tecidual , Titânio/química
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