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1.
Nihon Yakurigaku Zasshi ; 154(4): 210-216, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597901

RESUMO

Drug transporters play important roles in determining drug pharmacokinetics. Organic anion transporting polypeptides 1B1/1B3 (OATP1B1/1B3) are transporters mediating hepatic uptake of various anionic drugs. OATP1B1/1B3 activities are changed by genetic mutation and drug-drug interaction (DDI) that could lead to severe adverse reactions. Methods to address the precise DDI risk assessment have been developed in addition to the translational assessment from the results of in vitro studies. Using endogenous substrates as probes is an emerging approach that allows clinical assessment of the DDI risk in the early phase of drug development. Then, the clinical data will be subjected to the pharmacokinetic analysis using physiologically-based pharmacokinetic models to perform the more realistic DDI risk assessment with OATP1B1/1B3 substrate drugs. When drug targets are located inside the hepatocytes, DDI impact on the intrahepatic concentration is critical for their pharmacological actions. Positron emission tomography (PET) allows researchers to determine tissue concentration time profiles of the PET probe upon the inhibition of OATP1B1/1B3, and to estimate the change in kinetic parameter for each intrinsic process of hepatic elimination of PET probe. Integration of the clinical data into the PBPK model realizes more precise prediction of DDI impact on the pharmacokinetics of drugs, and their therapeutic effects.


Assuntos
Interações de Medicamentos , Transportador 1 de Ânion Orgânico Específico do Fígado/fisiologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/fisiologia , Humanos , Farmacocinética , Tomografia por Emissão de Pósitrons
2.
Nihon Yakurigaku Zasshi ; 154(3): 143-150, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527365

RESUMO

Quantitative systems pharmacology (QSP) is an emerging field of modeling technologies that describes the dynamic interaction between biological systems and drugs. Recently, QSP is increasingly being applied to pharmaceutical drug discovery and development, and used for various types of decision makings. In contrast to empirical and statistical models, QSP represents complex systems of human physiology by integrating comprehensive biological information, hence, it can address various purposes including target and/or disease-related biomarker identification, hypothesis testing, and prediction of clinical efficacy or toxicity. On the other hand, structures of QSP models become quite complicated with huge amount of biological components, therefore, close collaboration between pharmacologists having profound knowledge of biology and drug metabolism and pharmacokinetics (DMPK) scientists, experts of model building, is crucial for QSP development and implementation. This article introduces, from DMPK scientists to pharmacologists, main features of QSP and its applications in pharmaceutical industries, and discusses challenges and future perspectives for effective utilization in drug discovery and development.


Assuntos
Descoberta de Drogas/métodos , Modelos Biológicos , Farmacologia/métodos , Humanos , Farmacocinética , Projetos de Pesquisa
3.
Forensic Sci Int Genet. ; 42: 203-212, Sept., 2019. tab.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1022691

RESUMO

ABSTRACT: Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using mediumthroughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)


Assuntos
Farmacocinética , Predisposição Genética para Doença
4.
Pharm Res ; 36(10): 148, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414302

RESUMO

Medications have been used during space missions for more than half a century, yet our understanding of the effects of spaceflight on drug pharmacokinetics and pharmacodynamics is poor. The space environment induces time-dependent alterations in human physiology that include fluid shifts, cardiovascular deconditioning, bone and muscle density loss, and impaired immunity. This review presents the current knowledge on the physiological effects of spaceflight that can translate into altered drug disposition and activity and eventually to inadequate treatment. It describes findings from studies in astronauts along with mechanistic studies in animal models and in vitro systems. Future missions into deeper space and the emergence of commercial spaceflight will require a more detailed understanding of space pharmacology to optimize treatment in astronauts and space travelers.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Medicina Aeroespacial , Animais , Astronautas , Gravitação , Humanos , Farmacocinética , Voo Espacial , Ausência de Peso/efeitos adversos
5.
Nihon Yakurigaku Zasshi ; 154(2): 72-77, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406046

RESUMO

In drug disposition, the liver and small intestine are very important as tissues involving in drug metabolism, absorption, and excretion. Thus, in drug development studies, it is necessary to evaluate the pharmacokinetics in these tissues accurately including the contributions of drug-metabolizing enzymes and drug transporters. Currently, all kinds of evaluation systems have been used for the pharmacokinetic prediction; however, there are some issues in these systems. Therefore, the researches for the development of human induced pluripotent stem (iPS) cell-derived hepatocytes and enterocytes, as novel systems besides existing ones, are being advanced. Because human iPS cells have abilities of pluripotency and almost infinite proliferation, it is thought to be possible to stably provide the high-quality cells that have similar characteristics to human normal tissue cells by using human iPS cells. In this review, we describe current status of differentiation studies of human iPS cell-derived hepatocytes and enterocytes and the functional characteristics of these cells centered on pharmacokinetic functions.


Assuntos
Enterócitos/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Diferenciação Celular , Avaliação Pré-Clínica de Medicamentos , Enterócitos/citologia , Hepatócitos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Intestino Delgado , Fígado , Farmacocinética
6.
Emerg Med Clin North Am ; 37(3): 569-581, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31262422

RESUMO

The emergency department resuscitation of the critically ill geriatric patient is challenging and can be fraught with peril. The anatomic and physiologic changes that occur with aging can significantly influence the recognition of critical illness and the logistics of resuscitation itself. This article discusses the relevant physiologic changes with aging, the effect of these changes on clinical manifestations of critical illness in older adults, and the core principles of resuscitation in this population, with specific attention to sepsis and trauma care. In addition, end-of-life care is also discussed.


Assuntos
Estado Terminal/terapia , Serviço Hospitalar de Emergência , Ressuscitação , Idoso , Fenômenos Fisiológicos Cardiovasculares , Disfunção Cognitiva/complicações , Medicina de Emergência , Fragilidade/complicações , Avaliação Geriátrica , Taxa de Filtração Glomerular , Humanos , Hipnóticos e Sedativos/uso terapêutico , Imunossenescência , Limitação da Mobilidade , Manejo da Dor , Farmacocinética , Exame Físico , Fenômenos Fisiológicos Respiratórios , Sepse/diagnóstico , Sepse/terapia , Assistência Terminal , Equilíbrio Hidroeletrolítico , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia
7.
Artigo em Alemão | MEDLINE | ID: mdl-31344745

RESUMO

Under- or overdosage of medication can lead to severe side effects in children. To avoid this, precise knowledge of age-specific liberation, absorption, distribution, metabolism and excretion - LADME for short - is necessary. Absorption can take place intravenously, orally, rectally, intranasally, transdermally or epidurally/caudally and is associated with numerous special features in children, depending on age and route of application. The distribution in children is faster due to more permeable organ barriers between individual organs and must be adapted for hydrophilic and lipophilic drugs to the patient's age as well as their fat and fat-free body parts. Drug biotransformation takes place through Phase I and Phase II reactions, predominantly in the liver and kidneys. The cytochrome P450 (CYP450) enzyme system is the most important system for this and requires dose adjustment for numerous drugs in the first phase of life. Due to immature kidney function, all drugs with high renal clearance have a prolonged duration of action in the first months of life. Biliary excretion is particularly important for substances with a molecular weight of > 500 g/mol and is of limited functionality during the first months of life. The amount of substrate that is eliminated by the liver and kidneys within a defined period of time is known as clearance and is strongly dependent on the substance and age of the child. Reciprocal to this is the elimination half-life, which has to be considered especially with repetitive administration. Only with sufficient experience with pharmacokinetic variations or comedications within the different age groups, a patient-adapted, individually correct dose application is possible. The knowledge of the age-specific pharmacokinetics together with the knowledge of patient-specific peculiarities and comedications allow an individual drug application characterized by heuristics.


Assuntos
Preparações Farmacêuticas , Farmacocinética , Criança , Humanos , Rim , Fígado
8.
Expert Opin Drug Metab Toxicol ; 15(8): 633-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31274340

RESUMO

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. Areas covered: We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Transporte Biológico , Humanos , Lipídeos/química , Fígado/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ligação Proteica , Proteínas/metabolismo
9.
Forensic sci. int. ; 18(42): 203-212, Jul. 2019. gráfico, tabela
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1024428

RESUMO

Abstract Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analyzing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)


Assuntos
Arritmias Cardíacas/induzido quimicamente , Farmacocinética , Predisposição Genética para Doença , Ações Farmacológicas , Arritmias Cardíacas/genética
10.
Pharm Res ; 36(8): 113, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31152241

RESUMO

PURPOSE: To examine the interlaboratory variability in CLint values generated with human hepatocytes and determine trends in variability and clearance prediction accuracy using physicochemical and pharmacokinetic parameters. METHODS: Data for 50 compounds from 14 papers were compiled with physicochemical and pharmacokinetic parameter values taken from various sources. RESULTS: Coefficients of variation were as high as 99.8% for individual compounds and variation was not dependent on the number of prediction values included in the analysis. When examining median values, it appeared that compounds with a lower number of rotatable bonds had more variability. When examining prediction uniformity, those compounds with uniform in vivo underpredictions had higher CLint, in vivo values, while those with non-uniform predictions typically had lower CLint, in vivo values. Of the compounds with uniform predictions, only a small number were uniformly predicted accurately. Based on this limited dataset, less lipophilic, lower intrinsic clearance, and lower protein binding compounds yield more accurate clearance predictions. CONCLUSIONS: Caution should be taken when compiling in vitro CLint values from different laboratories as variations in experimental procedures (such as extent of shaking during incubation) may yield different predictions for the same compound. The majority of compounds with uniform in vitro values had predictions that were inaccurate, emphasizing the need for a better mechanistic understanding of IVIVE. The non-uniform predictions, often with low turnover compounds, reaffirmed the experimental challenges for drugs in this clearance range. Separating new chemical entities by lipophilicity, intrinsic clearance, and protein binding may help instill more confidence in IVIVE predictions.


Assuntos
Hepatócitos/metabolismo , Preparações Farmacêuticas/metabolismo , Farmacocinética , Fenômenos Químicos , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos , Humanos , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/química , Ligação Proteica
11.
Pharm Res ; 36(8): 114, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31152244

RESUMO

PURPOSE: Crewmembers aboard the International Space Station (ISS) have free access to an increasing number of medications within medical kits. The aim of the current study was to assess the number, severity and reliability of potential drug-drug interactions (DDIs) involving those medications. METHODS: We evaluated the information obtained from clinical decision support systems. Searches for potential DDIs were applied to published lists of medications available to US astronauts in medical kits aboard the ISS. RESULTS: A total of 311 potential DDIs were identified by Lexi-Interact, of which approximately half were recognized by Micromedex as well. Major, moderate and minor interactions consisted 23.5%, 68.5% and 8.0% of entries, respectively. The reliability of 71.1% of alerts was fair. Commonly used drugs, including zolpidem and zaleplon, were involved in multiple potential interactions that were classified as major based on additive CNS depression. CONCLUSIONS: Most potential DDIs likely to be encountered in space are unestablished even in terrestrial medicine and their assignment is based on class-effects. Yet, some drug combinations may be associated with clinically-relevant consequences. Future DDI rating should be adjusted to space-related outcomes. Until that happens, it would be advisable to avoid non-established drug combinations in space when possible.


Assuntos
Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Medicamentos sob Prescrição/metabolismo , Voo Espacial , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos , Humanos , Farmacocinética , Índice de Gravidade de Doença
12.
Life Sci ; 231: 116540, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176778

RESUMO

MRP4 is an ABC membrane transporter involved in clinical outcomes as it is located in many tissues that manages the transport and the elimination of many drugs. This review explores the implication of MRP4 in clinical pharmacology and the importance of its genetic variability. Although there is no specific recommendation regarding the study of MRP4 in drug development, it should be considered when drugs are eliminated by the kidney or liver or when drug-drug interactions are expected.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Animais , Antineoplásicos/farmacocinética , Antivirais/farmacocinética , Interações de Medicamentos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Farmacocinética , Farmacologia
13.
Chemosphere ; 229: 434-442, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082711

RESUMO

Estuaries routinely receive discharges of contaminants of emerging concern from urban regions. Within these dynamic estuarine systems, salinity and pH can vary across spatial and temporal scales. Our previous research identified bioaccumulation of the calcium channel blocker diltiazem and the antihistamine diphenhydramine in several species of fish residing in multiple urban estuaries along the Gulf of Mexico in Texas, where field-measured observations of diltiazem in fish plasma exceeded human therapeutic plasma doses. However, there remains a limited understanding of pharmaceutical bioaccumulation in estuarine environments. Here, we examined the influence of pH and salinity on bioconcentration of three pharmaceuticals in the Gulf killifish, Fundulus grandis. F. grandis were exposed to low levels of the ionizable pharmaceuticals carbamazepine, diltiazem, and diphenhydramine at two salinities (5 ppt, 20 ppt) and two pH levels (6.7, 8.3). pH influenced bioconcentration of select weak base pharmaceuticals, while salinity did not, suggesting that intestinal uptake via drinking does not appear to be a major exposure route of these pharmaceuticals in killifish. Compared to our previous pH dependent uptake observations with diphenhydramine in the fathead minnow model, killifish apparent volume of distribution values were markedly lower than fatheads, though killifish bioconcentration factors were similar at high pH and four fold higher at low pH than freshwater fish. Advancing an understanding of environmental gradient influences on pharmacokinetics among fish is necessary to improve bioaccumulation assessments and interpretation of toxicological observations for ionizable contaminants.


Assuntos
Estuários , Fundulidae/metabolismo , Concentração de Íons de Hidrogênio , Preparações Farmacêuticas/metabolismo , Salinidade , Animais , Carbamazepina/metabolismo , Diltiazem/metabolismo , Difenidramina/metabolismo , Golfo do México , Humanos , Farmacocinética , Texas , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/metabolismo
15.
Pharm Res ; 36(5): 76, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30937626

RESUMO

PURPOSE: Intranasal administration enhances drug delivery to the brain by allowing targeted-drug delivery. Here, we investigated the properties that render a compound suitable for intranasal administration, and the differences between rodents and non-human primates in delivery to the brain. METHODS: The delivery of 10 low-permeable compounds to the brain, including substrates of efflux drug transporters expressed in the blood-brain barrier (didanosine, metformin, zolmitriptan, cimetidine, methotrexate, talinolol, ranitidine, atenolol, furosemide, and sulpiride) and two high-permeable compounds (ropinirole and midazolam) was evaluated following intranasal and intravenous administration in rats. Six of the 12 compounds (metformin, cimetidine, methotrexate, talinolol, sulpiride, and ropinirole) were also evaluated in monkeys, which have a similar nasal cavity anatomical structure to humans. RESULTS: In rats, most of the low-permeable compounds displayed an obvious increase in the brain/plasma concentration ratio (Kp) by intranasal administration (despite their substrate liability for efflux drug transporters); this was not observed with the high-permeable compounds. Similarly, intranasal administration increased Kp for all low-permeable compounds in monkeys. CONCLUSIONS: Compound permeability is a key determinant of Kp increase by intranasal administration. This route of administration is more beneficial for low-permeable compounds and enhances their delivery to the brain in rodents and non-human primates.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/administração & dosagem , Administração Intranasal , Animais , Macaca fascicularis , Masculino , Membranas Artificiais , Bulbo Olfatório/metabolismo , Permeabilidade , Farmacocinética , Ratos , Ratos Sprague-Dawley
16.
Z Evid Fortbild Qual Gesundhwes ; 141-142: 66-73, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-30935788

RESUMO

Pharmacokinetic and pharmacodynamic models are mandatory for dosing and the safe use of drugs in the paediatric population. Different modelling methods allow for the development of dosing regimens for children requiring only a small number of blood samples or none at all. The medicines regulatory authorities recommend using these methods for paediatric drug development programs. Taking sildenafil as an example, the least invasive method of physiology-based pharmacokinetic simulation for the development of dosing regimens in the paediatric population is presented.


Assuntos
Desenvolvimento de Medicamentos , Modelos Biológicos , Criança , Alemanha , Humanos , Pediatria , Farmacocinética
18.
Yakugaku Zasshi ; 139(4): 565-570, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930389

RESUMO

When considering the use of pharmaceutical drugs during pregnancy and lactation, two concerns must be weighed against each other: the potential deleterious effects on the fetus and the possibility that treatment necessary for the woman but risky for the fetus either cannot be administered or else the woman must give up the pregnancy or give up nursing. The main roadblock to weighing these two concerns is a lack of evidence about what drugs are harmful to the fetus. Establishing this evidence is important to implementing the "Choosing Wisely" policy. In 2005, Japan established the Japan Drug Information Institute in Pregnancy (JDIIP), which addresses issues regarding treatments with pharmaceutical drugs during pregnancy and lactation. The JDIIP has analyzed data regarding the pregnancy results of patients who have received counseling and has conducted a registration survey, analyzed post-marketing survey data from pharmaceutical companies, and measured drug concentrations in breast milk. Currently, the JDIIP is increasing the number of targeted drugs about which it is collecting evidence. In addition, it is re-evaluating the published literature and implementing a project to revise drug packaging inserts. Pharmacists are expected to implement the "Choosing Wisely" policy regarding pharmaceutical treatment during pregnancy and lactation and to contribute to the collection of new evidence.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Medicina Baseada em Evidências , Prescrição Inadequada/prevenção & controle , Lactação , Sobremedicalização/prevenção & controle , Preparações Farmacêuticas , Gravidez , Serviços de Informação sobre Medicamentos , Rotulagem de Medicamentos , Feminino , Humanos , Japão , Troca Materno-Fetal , Leite Humano/metabolismo , Preparações Farmacêuticas/metabolismo , Farmacêuticos , Farmacocinética , Encaminhamento e Consulta
19.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978991

RESUMO

Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer's disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer's disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.


Assuntos
Harmina/química , Memantina/química , Farmacocinética , Receptores de N-Metil-D-Aspartato/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Interações de Medicamentos , Harmina/farmacocinética , Humanos , Memantina/farmacocinética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
20.
Yakugaku Zasshi ; 139(3): 437-460, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30828023

RESUMO

In this review, 9 compounds with insufficient absorption characteristics, safety or efficacy were selected from among the compounds for which the author was in charge of development between 2000 and 2005, in order to evaluate the pharmacokinetic (PK) approaches used to develop these compounds. Optimization of the PK characteristics of a compound at the early stage of chemical design was found to be the most important factor for successful development. For example, (i) selecting class I or II drugs in the biopharmaceutical classification system, while avoiding efflux transporters, and introducing an appropriate dissociation moiety into a compound to make it soluble lead to sufficient drug absorption; (ii) designing compounds whose production of reactive metabolites, such as acyl glucuronide, does not largely affect total metabolism, yet helps to prevent abnormal PK caused by reactive metabolites. Other factors include (i) selection of a drug efficacy evaluation system based on the correct understanding of the relationship between PK and pharmacodynamics (PD) helps to solve species differences in PD; (ii) the establishment of a nonclinical study based on the identification of the involvement of specific cytochrome P450 molecules in the total metabolic clearance of a drug (fm,CYPs) helps to solve species differences in PK; and (iii) PK analysis using the tube model for hepatic extraction kinetics, and knowledge of the fm,CYPs of the victim drug, lead to successful drug-drug interaction (DDI) prediction. I hope that this review aids in future drug discovery or development.


Assuntos
Descoberta de Drogas/métodos , Farmacocinética , Sistema Enzimático do Citocromo P-450 , Desenho de Drogas , Interações de Medicamentos , Humanos , Taxa de Depuração Metabólica , Modelos Biológicos
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