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1.
Emerg Med Clin North Am ; 38(4): 857-869, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981622

RESUMO

The obesity pandemic now affects hundreds of millions of people worldwide. As obesity rates continue to increase, emergency physicians are called on with increasing frequency to resuscitate obese patients. This article discusses important anatomic, physiologic, and practical challenges imposed by obesity on resuscitative care. Impacts on hemodynamic monitoring, airway and ventilator management, and pharmacologic therapy are discussed. Finally, several important clinical scenarios (trauma, cardiac arrest, and sepsis), in which alterations to standard treatments may benefit obese patients, are highlighted.


Assuntos
Obesidade/complicações , Ressuscitação/métodos , Manuseio das Vias Aéreas/métodos , Analgésicos/administração & dosagem , Antibacterianos/administração & dosagem , Composição Corporal , Fármacos Cardiovasculares/administração & dosagem , Doenças Cardiovasculares/complicações , Relação Dose-Resposta a Droga , Serviço Hospitalar de Emergência , Parada Cardíaca/terapia , Humanos , Hipnóticos e Sedativos/administração & dosagem , Medidas de Volume Pulmonar , Consumo de Oxigênio , Farmacocinética , Respiração com Pressão Positiva , Sepse/complicações , Sepse/terapia , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia
2.
Emerg Med Clin North Am ; 38(4): 919-930, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981626

RESUMO

The geriatric population is growing and is the largest utilizer of emergency and critical care services; the emergency clinician should be comfortable in the management of the acutely ill geriatric patient. There are important physiologic changes in geriatric patients, which alters their clinical presentation and management. Age alone should not determine the prognosis for elderly patients. Premorbid functional status, frailty, and severity of illness should be considered carefully for the geriatric population. Emergency clinicians should have honest conversations about goals of care based not only a patient's clinical presentation but also the patient's values.


Assuntos
Envelhecimento/fisiologia , Estado Terminal , Ressuscitação , Idoso , Cuidados Críticos , Tomada de Decisão Compartilhada , Delírio/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Serviço Hospitalar de Emergência , Fragilidade/classificação , Humanos , Farmacocinética , Polimedicação , Ordens quanto à Conduta (Ética Médica) , Assistência Terminal , Triagem
3.
Pharm Res ; 37(10): 194, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32918191

RESUMO

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Dibenzocicloeptenos/farmacologia , Dicetopiperazinas/farmacologia , Cães , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacologia , Especificidade por Substrato , Transfecção
4.
Lancet Gastroenterol Hepatol ; 5(9): 862-874, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818465

RESUMO

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Colestase/induzido quimicamente , Suplementos Nutricionais/efeitos adversos , Plantas Medicinais/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/terapia , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Farmacocinética , Fenótipo , Polimedicação , Fatores de Risco
5.
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
6.
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
7.
PLoS One ; 15(4): e0229639, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282831

RESUMO

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.


Assuntos
Acondroplasia/tratamento farmacológico , Meclizina/administração & dosagem , Meclizina/farmacocinética , Farmacocinética , Acondroplasia/sangue , Acondroplasia/patologia , Administração Oral , Animais , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Meclizina/sangue , Camundongos
8.
Pharmacol Rev ; 72(2): 414-438, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32123034

RESUMO

Technology in bioanalysis, -omics, and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs. SIGNIFICANCE STATEMENT: Over the past half century, pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) have evolved to provide an array of mechanism-based models that help quantitate the disposition and actions of most drugs. We describe how many basic PK and PK/PD model components were identified and often applied to the diverse properties of corticosteroids (CS). The CS have complications in disposition and a wide array of simple receptor-to complex gene-mediated actions in multiple organs. Continued assessments of such complexities have offered opportunities to develop models ranging from simple PK to enhanced PK/PD to quantitative systems pharmacology (QSP) that help explain therapeutic and adverse CS effects. Concurrent development of state-of-the-art PK, PK/PD, and QSP models are described alongside experimental studies that revealed diverse CS actions.


Assuntos
Corticosteroides/farmacologia , Corticosteroides/farmacocinética , Modelos Biológicos , Animais , Biologia Computacional/métodos , Humanos , Farmacocinética , Farmacologia/métodos
9.
Drug Metab Rev ; 52(1): 139-156, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32116054

RESUMO

There are more than 1000 species of microbes reside in the human gut, umbering∼1014 microbes. As the invisible organ of human beings, gut microbiota can usually participate in drug metabolism by producing specific enzymes, such as reductase and hydrolytic enzyme, thus affecting the efficacy, toxicity, and bioavailability of drugs. At least 30 commercially available drugs have been shown to be substrates of gut microbes-derived enzymes, and an increasing number of drugs may have the potential to contact with the distal gut with the help of improved release systems or poor solubility/permeability, more drugs are expected to be found to be metabolized through the gut flora. By collecting examples of intestinal flora participating in the metabolism of synthetic drugs and traditional Chinese medicine components, this article provides a comprehensive reference for future researchers to study drug metabolism by intestinal flora. Noticeably, the composition and quantity of intestinal flora varies among individuals, and can be affected by some drug administration (such as antibiotics) or environmental changes (acute plateau hypoxia). This seems to suggest that intestinal flora could have the potential to be a new drug target to affect the efficacy of drugs which can be metabolized by Intestinal flora. Accordingly, understanding the impact of intestinal flora on drug metabolism and clarifying the drug transformation process is of great significance for guiding rational clinical use, individualized use, toxicological evaluation, and promoting drug discovery and development.


Assuntos
Microbioma Gastrointestinal/fisiologia , Preparações Farmacêuticas/metabolismo , Animais , Medicamentos de Ervas Chinesas/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Farmacocinética
10.
Sci Adv ; 6(4): eaax2642, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32076633

RESUMO

Smart drug design for antibody and nanomaterial-based therapies allows optimization of drug efficacy and more efficient early-stage preclinical trials. The ideal drug must display maximum efficacy at target tissue sites, with transport from tissue vasculature to the cellular environment being critical. Biological simulations, when coupled with in vitro approaches, can predict this exposure in a rapid and efficient manner. As a result, it becomes possible to predict drug biodistribution within single cells of live animal tissue without the need for animal studies. Here, we successfully utilized an in vitro assay and a computational fluid dynamic model to translate in vitro cell kinetics (accounting for cell-induced degradation) to whole-body simulations for multiple species as well as nanomaterial types to predict drug distribution into individual tissue cells. We expect this work to assist in refining, reducing, and replacing animal testing, while providing scientists with a new perspective during the drug development process.


Assuntos
Simulação por Computador , Desenho de Fármacos , Modelos Biológicos , Farmacocinética , Animais , Linhagem Celular , Humanos
11.
Xenobiotica ; 50(9): 1023-1031, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31900032

RESUMO

Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/106 human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 µL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platform.This PBPK model was subsequently validated using reported maximum pemafibrate plasma concentration and area under the curve values in reported interaction studies in healthy subjects co-administered with rifampicin.For subjects with Child-Pugh A and B liver cirrhosis, the intrinsic clearance of hepatic uptake of pemafibrate by OATP1B1 were modeled using 53% and 31% of that of healthy subjects, respectively. Virtual co-administrations of rifampicin and sacubitril (OATP1B inhibitors) in subjects with renal impairment and liver cirrhosis resulted in 11- to 13-folds (rifampicin) and 1.1- to 1.3-folds (sacubitril) increased plasma exposures of pemafibrate.The current PBPK model and simulations revealed different pharmacokinetic profiles for pemafibrate following co-administration of rifampicin or sacubitril in virtual subjects with or without renal/hepatic impairment.


Assuntos
Benzoxazóis/sangue , Butiratos/sangue , Transporte Biológico , Interações Medicamentosas , Hepatócitos , Humanos , Rim/metabolismo , Fígado/metabolismo , Modelos Biológicos , Farmacocinética
12.
Nat Biomed Eng ; 4(4): 421-436, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31988459

RESUMO

Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.


Assuntos
Dispositivos Lab-On-A-Chip , Microfluídica/métodos , Preparações Farmacêuticas , Farmacocinética , Animais , Cisplatino/farmacocinética , Desenho de Fármacos , Humanos , Técnicas In Vitro , Fígado/metabolismo , Microfluídica/instrumentação , Modelos Biológicos , Nicotina/farmacocinética , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
13.
AAPS PharmSciTech ; 21(2): 44, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897807

RESUMO

The application and impact of human dose projection (HDP) has been well recognized in the late drug development phase, with increasing appreciation earlier during discovery and early development. This commentary describes the perspective of pharmaceutical scientists on the evolving application and impact of HDP at various phases from discovery to early development, including lead generation, lead optimization, lead up to candidate nomination, and early drug development. The underlying fundamental concepts and key input parameters for HDP are briefly discussed. A broad overview of phase-specific tools and approaches commonly utilized for human dose projection in the pharmaceutical industry is provided. A discussion of phase-appropriate implementation strategies, associated limitations/assumptions and continuous refinement for HDP from discovery to early development is presented. The authors describe the phase-specific applications of human dose projection to facilitate key assessments and relative impact on decision points.


Assuntos
Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Preparações Farmacêuticas/administração & dosagem , Animais , Química Farmacêutica , Relação Dose-Resposta a Droga , Desenho de Fármacos , Indústria Farmacêutica , Previsões , Humanos , Farmacocinética
14.
Xenobiotica ; 50(6): 663-669, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31638457

RESUMO

Pharmacokinetic studies are an integral part of drug discovery and development. Mice are the commonly used species for pharmacokinetics studies during early discovery studies. Conventionally, composite PK profiles are obtained from mice studies due to the physiological limitations of the total blood volume that can be drawn over a certain period.With advancements in bioanalytical instrumentation and in blood sampling techniques, analysis with small volume (<50 µL) became feasible enabling serial blood sampling from the mouse for PK studies. The objective of the current study was to develop and establish a serial blood sampling technique in mouse and compare it with the conventional sparse sampling method (composite PK) following oral administration of widely used NSAIDs, diclofenac, celecoxib and tenoxicam, into Swiss Albino mice.The pharmacokinetic parameters of all three probe drugs by serial blood sampling were comparable with that of sparse sampling method. There was no significant difference between the whole blood concentration time profiles of all three drugs between serial sampling and sparse sampling suggesting serial blood sampling method can be easily implemented for mice PK studies.Serial blood sampling technique requires use of fewer number of animals, less quantity of test compound and reduces the possible dosing errors as fewer number of animals need to be dosed resulting in quality PK data and enabling comparison of inter-animal differences in PK profile.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/sangue , Farmacocinética , Animais , Capilares , Descoberta de Drogas , Camundongos
15.
Xenobiotica ; 50(5): 526-535, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31491346

RESUMO

1. Immunodeficient chimeric mice with humanised liver have been useful in predicting total clearance values of drugs in humans. However, their usefulness may currently be limited for specific compounds with interspecies differences.2. In vivo total clearance and in vitro hepatic intrinsic clearance values of 16 model compounds were determined in control/humanised-liver mice and in mouse and human hepatocytes, respectively, for extrapolating the total clearance values of compounds in humans.3. The predictability of in vivo total clearance values of 11 model compounds in humans was adequate using pharmacokinetic data from humanised-liver mice. The predictability of total clearance values using humanised-liver mice was better than conventional allometric scaling for compounds with large interspecies differences in in vitro hepatic intrinsic clearance or plasma unbound fractions.4. There were trends that total clearance values in control and humanised-liver mice were similar to or higher than reported hepatic blood flow rates in normal mice among four compounds with poor predictability. Diazepam, with the poorest predictability, showed 38-fold-higher hepatic intrinsic clearance in mice than in humans.5. These results could lead to guidelines describing that compounds may be suited or unsuited to extrapolating total clearance values in humans from pharmacokinetics in humanised-liver mice.


Assuntos
Taxa de Depuração Metabólica , Modelos Biológicos , Animais , Quimera , Hepatócitos , Humanos , Cinética , Fígado , Camundongos , Microssomos Hepáticos , Farmacocinética , Ligação Proteica , Especificidade da Espécie
16.
Xenobiotica ; 50(3): 288-296, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31181990

RESUMO

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.


Assuntos
Cilostazol/metabolismo , Inibidores da Fosfodiesterase 3/metabolismo , Adulto , Disponibilidade Biológica , Cilostazol/administração & dosagem , Feminino , Humanos , Masculino , Farmacocinética , Inibidores da Fosfodiesterase 3/administração & dosagem , República da Coreia
17.
J Anal Toxicol ; 44(2): 109-125, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31682266

RESUMO

Cannabis products in which cannabidiol (CBD) is the primary chemical constituent (CBD-dominant) are increasingly popular and widely available. The impact of CBD exposure on urine drug testing has not been well studied. This study characterized the urinary pharmacokinetic profile of 100-mg oral and vaporized CBD, vaporized CBD-dominant cannabis (100-mg CBD; 3.7-mg ∆9-THC) and placebo in healthy adults (n = 6) using a within-subjects crossover design. Urine specimens were collected before and for 5 days after drug administration. Immunoassay (IA) screening (cutoffs of 20, 50 and 100 ng/mL) and LC-MS-MS confirmatory tests (cutoff of 15 ng/mL) for 11-nor-9-carboxy-∆9-tetrahydrocannabinol (∆9-THCCOOH) were performed; urine was also analyzed for CBD and other cannabinoids. Urinary concentrations of CBD were higher after oral (mean Cmax: 776 ng/mL) versus vaporized CBD (mean Cmax: 261 ng/mL). CBD concentrations peaked 5 h after oral CBD ingestion and within 1 h after inhalation of vaporized CBD. After pure CBD administration, only 1 out of 218 urine specimens screened positive for ∆9-THCCOOH (20-ng/mL IA cutoff) and no specimens exceeded the 15-ng/mL confirmatory cutoff. After inhalation of CBD-dominant cannabis vapor, nine samples screened positive at the 20-ng/mL IA cutoff, and two of those samples screened positive at the 50-ng/mL IA cutoff. Four samples that screened positive (two at 20 ng/mL and two at 50 ng/mL) confirmed positive with concentrations of ∆9-THCCOOH exceeding 15 ng/mL. These data indicate that acute dosing of pure CBD will not result in a positive urine drug test using current federal workplace drug testing guidelines (50-ng/mL IA cutoff with 15-ng/mL confirmatory cutoff). However, CBD products that also contain ∆9-THC may produce positive urine results for ∆9-THCCOOH. Accurate labeling and regulation of ∆9-THC content in CBD/hemp products are needed to prevent unexpected positive drug tests and unintended drug effects.


Assuntos
Canabidiol/urina , Canabinoides/urina , Administração por Inalação , Administração Oral , Adulto , Canabidiol/farmacocinética , Canabinoides/farmacocinética , Estudos Cross-Over , Feminino , Humanos , Masculino , Fumar Maconha , Farmacocinética , Volatilização
18.
Xenobiotica ; 50(5): 545-551, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31524030

RESUMO

Hydroxysafflor yellow A (HSYA) is the most pharmaceutically relevant compound in Xuebijing (XBJ) for traumatic brain injury (TBI) treatment. We aimed to investigate biofluids pharmacokinetics of HSYA from XBJ to ensure the drug safety and to guide the clinical use.A sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to investigate pharmacokinetics of HSYA in TBI patients after intravenous administration of XBJ. Non-compartmental methods using DAS 3.0 software were applied to analyse the pharmacokinetic parameters.A similar half-life (Plasmat1/2: 14.55 ± 3.51 h vs. CSFt1/2: 15.73 ± 3.63) was observed. HSYA reached the peak level rapidly, but exhibited a strongly slow absorption phase from blood to cerebrospinal fluid (CSF, PlasmaTmax: 0.69 ± 0.26 h vs. CSFTmax: 4.0 ± 2.62 h). HSYA exhibited much higher Cmax (PlasmaCmax: 9342.76 ± 2489.23 µg/L vs. CSFCmax: 98.08 ± 14.51 µg/L) and AUC0-t (PlasmaAUC0-t: 57490.5 ± 5560.3 µg h/L vs. CSFAUC0-t: 1851.6 ± 269.1 µg h/L), yet a shorter CL (PlasmaCL: 0.02 ± 0.002 L/h/kg vs. CSFCL: 0.55 ± 0.01 L/h/kg) in plasma than in CSF. The AUCCSF/AUCplasma of HSYA was almost 3.37%.In summary, the results demonstrate that part of HSYA come across blood-brain barrier after XBJ administration. This study provides evidence for better understanding the pharmacokinetics and potential for clinical guidance of XBJ for TBI treatment.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Chalcona/análogos & derivados , Medicamentos de Ervas Chinesas/metabolismo , Quinonas/metabolismo , Administração Intravenosa , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Chalcona/sangue , Chalcona/líquido cefalorraquidiano , Chalcona/metabolismo , Humanos , Farmacocinética , Quinonas/sangue , Quinonas/líquido cefalorraquidiano
19.
Toxicol Lett ; 319: 95-101, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678400

RESUMO

Physiologically based kinetic (PBK) models for farm animals are of growing interest in food and feed safety with key applications for regulated compounds including quantification of tissue concentrations, kinetic parameters and the setting of safe exposure levels on an internal dose basis. The development and application of these models requires data for physiological, anatomical and chemical specific parameters. Here, we present the results of a structured data collection of anatomical and physiological parameters in three key farm animal species (swine, cattle and sheep). We performed an extensive literature search and meta-analyses to quantify intra-species variability and associated uncertainty of the parameters. Parameters were collected for organ weights and blood flows in all available breeds from 110 scientific publications, of which 29, 48 and 33 for cattle, sheep, and swine, respectively. Organ weights were available in literature for all three species. Blood flow parameter values were available for all organs in sheep but were scarcer in swine and cattle. Furthermore, the parameter values showed a large intra-species variation. Overall, the parameter values and associated variability provide reference values which can be used as input for generic PBK models in these species.


Assuntos
Animais Domésticos/metabolismo , Bovinos/metabolismo , Farmacocinética , Carneiro Doméstico/metabolismo , Suínos/metabolismo , Animais , Peso Corporal/fisiologia , Bovinos/anatomia & histologia , Modelos Biológicos , Tamanho do Órgão/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Carneiro Doméstico/anatomia & histologia , Especificidade da Espécie , Suínos/anatomia & histologia
20.
Drug Deliv ; 27(1): 110-127, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885288

RESUMO

Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.


Assuntos
Excipientes/química , Farmacocinética , Tecnologia Farmacêutica/métodos , Disponibilidade Biológica , Cristalização , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Solubilidade , Tensoativos/química
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