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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
J Pharmacol Exp Ther ; 372(3): 308-319, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31879375

RESUMO

Within the drug pharmacokinetics (PK)-absorption, distribution, metabolism, and excretion (ADME) research community, investigators regularly generate in vitro data sets using appropriately vendor-sourced and processed human tissue. Such data enable drug screening, the generation of kinetic parameters, extrapolation of in vitro to in vivo, as well as the modeling and simulation of drug PK. Although there are large numbers of manuscripts describing studies with deceased organ donor tissue, relatively few investigators have published studies utilizing living donor tissue biopsy samples. After a review of the available literature, it was possible to find publications describing the use of tissue biopsy samples to determine enzyme inhibition ex vivo, the study of genotype-phenotype associations, the evaluation of tissue expression profiling following an inducer, and assessment of correlations between tissue expression profiles and in vivo-derived trait measures (e.g., biomarker plasma levels and probe drug PK). Some reports described multiple single-tissue biopsies, whereas others described single multiple-organ biopsies. It is concluded that biopsy-derived data can support modeling exercises (as input data and when validating models) and enable the assessment of organ-specific changes in enzyme and transporter profiles resulting from drug interactions, disease (e.g., metabolic disease, fibrosis, inflammation, cancer, infection), age, pregnancy, organ impairment, and genotype. With the emergence of multiorgan axes (e.g., microbiome-gut-liver-kidney) and interest in remote sensing (interorgan communication), it is envisioned that there will be increased demand for single- and multiorgan tissue biopsy data to support hypothesis testing and PK-ADME model building. SIGNIFICANCE STATEMENT: Based on a review of the literature, it is apparent that profiling of human tissue biopsy samples is useful in support of pharmacokinetics (PK)-absorption, distribution, metabolism, and excretion (ADME)-related studies. With conventional tissue biopsy as precedent, it is envisioned that researchers will turn to less invasive "liquid biopsy" methods in support of ADME-related studies (e.g., profiling of plasma-derived tissue-specific nanovesicles). Generation of such multiorgan liquid biopsy data in larger numbers of subjects and at multiple study time points will provide a rich data set for modeling purposes.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Fígado/enzimologia , Proteínas de Membrana Transportadoras/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Biópsia , Humanos , Taxa de Depuração Metabólica , Preparações Farmacêuticas/sangue , Farmacocinética , Distribuição Tecidual
13.
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
14.
Expert Opin Drug Metab Toxicol ; 15(12): 1005-1019, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31794278

RESUMO

Introduction: After administration, a drug undergoes absorption, distribution, metabolism, and elimination (ADME) before exerting its effect on the body. The combination of these process yields the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of a drug. Although accurate prediction of PK and PD profiles is essential for drug development, conventional in vitro models are limited by their lack of physiological relevance. Recently, microtechnology-based in vitro model systems, termed 'organ-on-a-chip,' have emerged as a potential solution.Areas covered: Orally administered drugs are absorbed through the intestinal wall and transported to the liver before entering systemic circulation, which plays an important role in the PK and PD profiles. Recently developed, chip-based in vitro models can be useful models for simulating such processes and will be covered in this paper.Expert opinion: The potential of intestine-on-a-chip models combined with conventional PK-PD modeling has been demonstrated with promising preliminary results. However, there are several challenges to overcome. Development of the intestinal wall, integration of the gut microbiome, and the provision of an intestine-specific environment must be achieved to realize in vivo-like intestinal model and enhance the efficiency of drug development.


Assuntos
Desenvolvimento de Medicamentos/métodos , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Administração Oral , Animais , Humanos , Absorção Intestinal , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética
15.
Nihon Yakurigaku Zasshi ; 154(6): 345-351, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787688

RESUMO

MPS (microphysiological system) is in-vitro cell-culture environment, which is precisely maintained in a micro space manufactured using MEMS (micro electro mechanical systems) technology, to derive in-vivo like functions from human cells. From the viewpoint of pharmacokinetics, it can be considered as a wet PBPK/PD simulator consisting of the micro organs (cell culture units) connected each other with a circulating medium, which mimic the organs responsible for the drug's ADME (absorption-distribution-metabolism-elimination). In this review, we identify two types of the cell culture units consisting of the MPS for pharmacokinetics, and overview the characteristics of each type. Then, we discuss about the technical requirements needed for the cell culture unit from the point of view of both cell-culture environmental design and cell function, and introduce the world-wide current situation of the commercialization of the MPS.


Assuntos
Técnicas de Cultura de Células , Sistemas de Liberação de Medicamentos , Humanos , Farmacocinética , Tecnologia
16.
Pharm Res ; 37(1): 12, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873819

RESUMO

Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. The latter is likely due to sparsity of information regarding pharmacokinetics of pharmacological agents and the mechanisms through which agents get systemic exposure after IP administration. In this review, we summarize the main mechanisms involved in bioavailability of IP administered drugs and provide examples of pharmacokinetic profiles for small and large molecules in comparison to other routes of administration. We conclude with a notion that IP administration of drugs in experimental studies involving rodents is a justifiable route for pharmacological and proof-of-concept studies where the goal is to evaluate the effect(s) of target engagement rather than properties of a drug formulation and/or its pharmacokinetics for clinical translation.


Assuntos
Composição de Medicamentos/métodos , Injeções Intraperitoneais/métodos , Preparações Farmacêuticas/química , Animais , Disponibilidade Biológica , Vias de Administração de Medicamentos , Humanos , Injeções Subcutâneas/métodos , Modelos Animais , Tamanho da Partícula , Farmacocinética , Transdução de Sinais
17.
Ups J Med Sci ; 124(4): 218-227, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31724901

RESUMO

Clinical trial results of phage treatment of bacterial infections show a low to moderate efficacy, and the variation in infection clearance between subjects within studies is often large. Phage therapy is complicated and introduces many additional components of variance as compared to antibiotic treatment. A large part of the variation is due to in vivo pharmacokinetics and pharmacodynamics being virtually unknown, but also to a lack of standardisation. This is a consequence of the great variation of phages, bacteria, and infections, which results in different experiments or trials being impossible to compare, and difficulties in estimating important parameter values in a quantitative and reproducible way. The limitations of phage therapy will have to be recognised and future research focussed on optimising infection clearance rates by e.g. selecting phages, bacteria, and target bacterial infections where the prospects of high efficacy can be anticipated, and by combining information from new mathematical modelling of in vivo pharmacokinetic and pharmacodynamic processes and quantitatively assessed experiments.


Assuntos
Infecções Bacterianas/terapia , Bacteriófagos , Terapia por Fagos/métodos , Animais , Antibacterianos/uso terapêutico , Humanos , Técnicas In Vitro , Modelos Teóricos , Otite Média/microbiologia , Otite Média/terapia , Farmacocinética , Pseudomonas aeruginosa , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Nat Commun ; 10(1): 5031, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695028

RESUMO

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.


Assuntos
Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/farmacologia , Engenharia de Proteínas , Receptores Fc/química , Receptores Fc/genética , Animais , Engenharia Genética , Meia-Vida , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Concentração de Íons de Hidrogênio , Imunoglobulina G/química , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Farmacocinética , Domínios Proteicos , Receptores Fc/imunologia , Proteínas Recombinantes
19.
Curr Top Med Chem ; 19(29): 2643-2657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31702504

RESUMO

Different kinds of biological activities are defined by complex biochemical interactions, which are termed as a "mathematical function" not only of the molecular structure but also for some additional circumstances, such as physicochemical conditions, interactions via energy and information effects between a substance and organisms, organs, cells. These circumstances lead to the great complexity of prediction for biochemical endpoints, since all "details" of corresponding phenomena are practically unavailable for the accurate registration and analysis. Researchers have not a possibility to carry out and analyse all possible ways of the biochemical interactions, which define toxicological or therapeutically attractive effects via direct experiment. Consequently, a compromise, i.e. the development of predictive models of the above phenomena, becomes necessary. However, the estimation of the predictive potential of these models remains a task that is solved only partially. This mini-review presents a collection of attempts to be used for the above-mentioned task, two special statistical indices are proposed, which may be a measure of the predictive potential of models. These indices are (i) Index of Ideality of Correlation; and (ii) Correlation Contradiction Index.


Assuntos
Modelos Biológicos , Farmacocinética , Testes de Toxicidade , Humanos , Método de Monte Carlo , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Software
20.
Curr Top Med Chem ; 19(29): 2687-2707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31702505

RESUMO

BACKGROUND: Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are a class of C GPCRs that play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain involved in cognition, learning, memory, and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, X-fragile syndrome, anxiety, depression, etc., hence these receptors are high profile targets for pharmaceutical industries. OBJECTIVE: The objective of our study is to find the novel dual negative allosteric modulators to regulate both mGluR1 and mGluR5. METHODS: In this study, shape screening protocol was used to find the dual negative allosteric modulators for both mGluR1 and mGluR5 followed by ADME prediction, induced-fit docking (IFD) and molecular dynamics simulations. Further, DFT analysis and MESP studies were carried out for the selected compounds. RESULTS: Around 247 compounds were obtained from the eMolecules database and clustered through the CANVAS module and filtered with ADME properties. Furthermore, IFD revealed that the top four compounds (16059796, 25004252, 4667236 and 11670690) having good protein-ligand interactions and binding free energies. The molecular electrostatic potential of the top compounds shows interactions in the amine group and the oxygen atom in the negative potential regions. Finally, molecular dynamics simulations were performed with all the selected as well as the reported compound 29 indicates that the screened hits have better stability of protein ligand complex. CONCLUSION: Hence, from the results, it is evident that top hits 16059796, 25004252, 4667236 and 11670690 could be a novel and potent dual negative allosteric modulators for mGluR1 and mGluR5.


Assuntos
Doenças Neurodegenerativas/terapia , Farmacocinética , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Humanos , Ligantes , Simulação de Dinâmica Molecular , Doenças Neurodegenerativas/metabolismo
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