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2.
Clin Drug Investig ; 39(12): 1223-1232, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31552642

RESUMO

BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Pirazóis/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Sulfonamidas/farmacologia , Adolescente , Adulto , Interações de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Int J Clin Pharmacol Ther ; 57(12): 612-622, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549624

RESUMO

CONTEXT: A fixed-dose combination (FDC) tablet of amlodipine and rosuvastatin was recently developed for the treatment of concomitant hypertension and dyslipidemia and is anticipated to improve medication compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and safety of DP-R212 (FDC of amlodipine and rosuvastatin) to those of each agent co-administered in healthy Korean subjects. MATERIALS AND METHODS: A total of 36 healthy Korean subjects were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test drug (FDC tablet containing amlodipine and rosuvastatin) or reference drugs (individual tablets). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post-dose. Safety was assessed by the evaluation of adverse events (AEs), laboratory assessments, 12-lead electrocardiograms (ECGs), physical examinations, and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of AUClast and Cmax were 0.9796 - 1.0590 and 1.0135 - 1.0981 for amlodipine, and 0.9156 - 1.0490 and 0.8400 - 1.0306 for rosuvastatin, respectively. All AEs were of mild to moderate intensity, and no significant difference was observed in the incidence of AEs between the treatments. Moreover, the pharmacokinetic properties of the test and reference drugs were bioequivalent to each other, satisfying the regulatory criteria (0.8 - 1.25). DISCUSSION AND CONCLUSION: Both drugs were safe and well tolerated, and the pharmacokinetic profiles were comparable between the treatments.


Assuntos
Anlodipino/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem , Administração Oral , Anlodipino/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Quimioterapia Combinada , Voluntários Saudáveis , Humanos , República da Coreia , Rosuvastatina Cálcica/farmacocinética , Comprimidos , Equivalência Terapêutica
4.
Artigo em Inglês | MEDLINE | ID: mdl-31374423

RESUMO

Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.


Assuntos
Anlodipino/sangue , Atorvastatina/sangue , Infecções por HIV , Metoprolol/sangue , Pravastatina/sangue , Rosuvastatina Cálcica/sangue , Anlodipino/química , Anlodipino/metabolismo , Anlodipino/farmacocinética , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Atorvastatina/química , Atorvastatina/metabolismo , Atorvastatina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Interações de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Modelos Lineares , Metoprolol/química , Metoprolol/metabolismo , Metoprolol/farmacocinética , Pravastatina/química , Pravastatina/metabolismo , Pravastatina/farmacocinética , Reprodutibilidade dos Testes , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
5.
Drug Dev Ind Pharm ; 45(10): 1635-1645, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342792

RESUMO

Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability. Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, 1H-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3 months. Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13 nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08 × 10-7 cm⋅s-1 Papp value) while CPNs gained higher permeability data (1.36 × 10-5 and 1.12 × 10-5 cm⋅s-1 Papp values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved. Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability.


Assuntos
Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Nanopartículas/química , Polianidridos/química , Polianidridos/farmacocinética , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Animais , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
6.
Int J Nanomedicine ; 14: 4625-4636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303752

RESUMO

Purpose: Rosuvastatin calcium (ROSCa) nanoparticles were fabricated by planetary ball mill to enhance ROSCa dissolution rate and bioavailability. Methods: Milling time factors (milling cycle time and number as well as pause time) were explored. The effect of different milling ball size, speed, and solid-to-solvent ratio were also studied using Box-Behnken factorial design. The fabricated nanoparticles were evaluated in term of physicochemical properties and long-term stability. Results: The obtained data revealed that the integrated formulation and process factors should be monitored to obtain desirable nanoparticle attributes in terms of particle size, zeta potential, dissolution rate, and bioavailability. The optimized ROSCa nanoparticles prepared by milling technique showed a significant enhancement in the dissolution rate by 1.3-fold and the plasma concentration increased by 2-fold (P<0.05). Moreover, stability study showed that the optimized formula of ROSCa nanoparticles exhibits higher stability in long-term stability conditions at 30°C with humidity of 60%. Conclusion: Formulation of ROSCa as nanoparticles using milling technique showed a significant enhancement in both dissolution rate and plasma concentration as well as stability compared with untreated drug.


Assuntos
Nanopartículas/química , Nanotecnologia/métodos , Rosuvastatina Cálcica/química , Animais , Estabilidade de Medicamentos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Rosuvastatina Cálcica/sangue , Rosuvastatina Cálcica/farmacocinética , Eletricidade Estática , Fatores de Tempo
7.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
8.
J Pharm Biomed Anal ; 174: 226-234, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31181484

RESUMO

The synergistic vascular protective effect of statins and angiotensin receptor blockers (ARBs) is well known, however, the pharmacokinetic interaction among these classes is yet to be understood and the necessity of developing analytical methods for their determination in vivo is gradually increased. Herein, first chromatographic separation coupled tandem mass spectrometric was developed and fully validated for simultaneous measurement of rosuvastatin (ROS) and irbesartan (IRB) in rat plasma after oral administration. The two analytes were extracted from plasma sample using acetonitrile-induced protein precipitation then separated on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column by gradient elution using 6 mM ammonium formate/0.1% formic acid and ACN at a flow rate 0.4 mL min-1. Multiple reaction monitoring in positive ion mode was used for quantification of precursor to production at m/z 492.1 → 206.9 for IRB, 482.1 → 258.1 for ROS, and 409.2 → 238.2 for the internal standard, amlodipine (AML). Linearity was obeyed in the range of 1-10000 ng mL-1 and 1-5000 ng mL-1 with detection limits (S/N of 3) of 0.05 and 0.07 ng mL-1 for IRB and ROS, respectively. The current method was validated in terms of selectivity, recovery, accuracy, precision, matrix effects, and stability as per US-FDA bioanalytical guidelines. The application of our method reported her is the first to study pharmacokinetic interaction of IRB and ROS in rat plasma after a single oral dose. The area under the concentration-time curve (AUC), peak plasma concentrations (Cmax), half-life time (t1/2), and volume of distribution (Vd) of ROS and IRB were affected when the two drugs were co-administering. The current study provided a valuable tool for studying drug-drug interaction and might be useful for therapeutic drug monitoring and bioequivalence studies.


Assuntos
Cromatografia Líquida/métodos , Irbesartana/sangue , Irbesartana/farmacocinética , Rosuvastatina Cálcica/sangue , Rosuvastatina Cálcica/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Área Sob a Curva , Calibragem , Interações de Medicamentos , Monitoramento de Medicamentos , Limite de Detecção , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes
9.
Biomed Chromatogr ; 33(10): e4607, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31141832

RESUMO

A simple, precise and accurate HPLC method was developed, optimized and validated for simultaneous determination of rosuvastatin and candesartan in rat plasma using atorvastatin as an internal standard. Solid-phase extraction was used for sample cleanup and its subsequent optimization was carried out to achieve higher extraction efficiency and to eliminate matrix effect. A quality by design approach was used, wherein three-level factorial design was applied for optimization of mobile phase composition and for assessing the effect of pH of the mobile phase using Design Expert Software. Adequate separation for both analytes was achieved with a Waters C18 column (250 × 4.6 mm, 5 µm) using acetonitrile-5 mm sodium acetate buffer (70:30, v/v; pH adjusted to 3.5 with acetic acid) as a mobile phase at a flow rate of 1.0 mL/min and wavelength of 254 nm. The calibration curves were linear over the concentration ranges 5-150 and 10-300 ng/mL for rosuvastatin (ROS) and candesartan (CAN), respectively. The validated method was successfully applied to a pharmacokinetic study in Wistar rats and the data did not reveal any evidence for a potential drug-drug interaction between ROS and CAN. This information provides evidence for clinical rational use of ROS and CAN.


Assuntos
Benzimidazóis/sangue , Cromatografia Líquida de Alta Pressão/métodos , Rosuvastatina Cálcica/sangue , Tetrazóis/sangue , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sensibilidade e Especificidade , Extração em Fase Sólida , Tetrazóis/química , Tetrazóis/farmacocinética
10.
Drug Des Devel Ther ; 13: 991-997, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114155

RESUMO

Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.


Assuntos
Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Adulto , Anlodipino/sangue , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Imidazóis/sangue , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Rosuvastatina Cálcica/sangue , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , Tetrazóis/sangue , Adulto Jovem
11.
Expert Opin Drug Metab Toxicol ; 15(4): 313-328, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30856014

RESUMO

INTRODUCTION: ABCG2 has a broad substrate specificity and is one of the most important efflux proteins modulating pharmacokinetics of drugs, nutrients and toxicokinetics of toxicants. ABCG2 is an important player in transporter-mediated drug-drug interactions (tDDI). Areas covered: The aims of the review are i) to cover transporter interaction profile of substrates and inhibitors that can be utilized to test interaction of drug candidates with ABCG2, ii) to highlight main characteristics of in vitro testing and iii) to describe the structural basis of the broad substrate specificity of the protein. Preclinical data utilizing Abcg2/Bcrp1 knockouts and clinical studies showing effect of ABCG2 c.421C>A polymorphism on pharmacokinetics of drugs have provided evidence for a broad array of drug substrates and support drug - ABCG2 interaction testing. A consensus on using rosuvastatin and sulfasalazine as intestinal substrates for clinical studies is in the formation. Other substrates relevant to the therapeutic area can be considered. Monolayer efflux assays and vesicular transport assays have been extensively utilized in vitro. Expert opinion: Clinical substrates display complex pharmacokinetics due to broad interaction profiles with multiple transporters and metabolic enzymes. Substrate-dependent inhibition has been observed for several inhibitors. Harmonization of in vitro and in vivo testing makes sense. However, rosuvastatin and sulfasalazine are not efficiently transported in either MDCKII or LLC-PK1-based monolayers. Caco-2 monolayer assays and vesicular transport assays are potential alternatives.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Preparações Farmacêuticas/metabolismo , Farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico/fisiologia , Células CACO-2 , Interações de Medicamentos , Técnicas de Inativação de Genes , Humanos , Proteínas de Neoplasias/genética , Preparações Farmacêuticas/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Especificidade por Substrato , Sulfassalazina/farmacocinética , Toxicocinética
12.
Biopharm Drug Dispos ; 40(3-4): 135-150, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30921829

RESUMO

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.


Assuntos
Grupo com Ancestrais do Continente Asiático , Modelos Biológicos , Software , Adulto , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Lorazepam/farmacocinética , Masculino , Metoprolol/farmacocinética , Midazolam/farmacocinética , Pessoa de Meia-Idade , Omeprazol/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Varfarina/farmacocinética , Adulto Jovem
13.
Xenobiotica ; 49(2): 239-246, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29405807

RESUMO

1. Deoxyschizandrin and schizandrin B have diverse pharmacological effects, including hepatoprotective activity. We aim to study their hepatic uptake and their effects on the hepatic uptake of other clinical drugs mediated by OATP1B1 and OATP1B3. 2. Deoxyschizandrin exhibited a high affinity for OATP1B1 with Km of 17.61 ± 0.43 µM but a low affinity for OATP1B3. Similarly, schizandrin B also showed a strong affinity for OATP1B1 with Km of 18.45 ± 1.23 µM but a weak affinity for OATP1B3. 3. Atorvastatin and rifampicin could inhibit the uptake of deoxyschizandrin and schizandrin B mediated by OATP1B1. 4. Intriguingly, both deoxyschizandrin and schizandrin B significantly promoted the uptake of atorvastatin (with EC50 of 50.58 ± 8.08 and 24.70 ± 5.82 µM, respectively) and rosuvastatin (with EC50 of 13.46 ± 2.70 and 8.99 ± 4.73 µM, respectively) mediated by OATP1B1. Deoxyschizandrin could markedly promote the uptake of fluvastatin but inhibit the uptake of sodium taurocholate (TCNa) mediated by OATP1B1. 5. The promotion on hepatic uptake of statins mediated by OATP1B1 might lead to enhanced efficacy of cholesterol lowering and reduced risk of myopathy for hyperlipidemia patients when given statins together with deoxyschizandrin or schizandrin B.


Assuntos
Ciclo-Octanos/farmacocinética , Lignanas/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Compostos Policíclicos/farmacocinética , Substâncias Protetoras/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Atorvastatina/efeitos adversos , Atorvastatina/farmacocinética , Ciclo-Octanos/metabolismo , Interações de Medicamentos , Células HEK293 , Humanos , Cinética , Lignanas/metabolismo , Compostos Policíclicos/metabolismo , Substâncias Protetoras/metabolismo , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética
14.
Xenobiotica ; 49(10): 1221-1228, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29944058

RESUMO

Radix Ophiopogonis is often an integral part of many traditional Chinese formulas, such as Shenmai injection used to treat cardio-cerebrovascular diseases. This study aimed to investigate the influence of the four active components of Radix Ophiopogonis on the transport activity of OATP1B1 and OATP1B3. The uptake of rosuvastatin in OATP1B1-HEK293T cells were stimulated by methylophiopogonanone A (MA) and ophiopogonin D' (OPD') with EC50 calculated to be 11.33 ± 2.78 and 4.62 ± 0.64 µM, respectively. However, there were no remarkable influences on rosuvastatin uptake in the presence of methylophiopogonanone B (MB) or ophiopogonin D (OPD). The uptake of atorvastatin in OATP1B1-HEK293T cells can be increased by MA, MB, OPD and OPD' with EC50 calculated to be 6.00 ± 1.60, 13.64 ± 4.07, 10.41 ± 1.28 and 3.68 ± 0.85 µM, respectively. The uptake of rosuvastatin in OATP1B3-HEK293T cells was scarcely influenced by MA, MB and OPD, but was considerably increased by OPD' with an EC50 of 14.95 ± 1.62 µM. However, the uptake of telmisartan in OATP1B3-HEK293T cells was notably reduced by OPD' with an IC50 of 4.44 ± 1.10 µM, and barely affected by MA, MB and OPD. The four active components of Radix Ophiopogonis affect the transporting activitives of OATP1B1 and OATP1B3 in a substrate-dependent manner.


Assuntos
Atorvastatina , Benzodioxóis , Isoflavonas , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Ranunculaceae/química , Rosuvastatina Cálcica , Saponinas , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Espirostanos , Atorvastatina/farmacocinética , Atorvastatina/farmacologia , Benzodioxóis/química , Benzodioxóis/farmacologia , Células HEK293 , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/farmacologia , Saponinas/química , Saponinas/farmacologia , Espirostanos/química , Espirostanos/farmacologia
15.
Acta Pharmacol Sin ; 40(4): 492-499, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29950617

RESUMO

Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and N-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performance liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (Padj < 0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (Padj < 0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% CI: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 0.406-0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n = 707) (all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.


Assuntos
Amidinotransferases/genética , Doença da Artéria Coronariana/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Doenças Musculares/induzido quimicamente , Rosuvastatina Cálcica/sangue , Amidinotransferases/sangue , Amidinotransferases/metabolismo , China , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Variação Genética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Doenças Musculares/genética , Polimorfismo de Nucleotídeo Único/genética , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética
16.
Farm. comunitarios (Internet) ; 10(4): 29-32, 28 dic., 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-175294

RESUMO

En ancianos es frecuente la polimedicación. Esto incrementa el riesgo de sufrir reacciones adversas a los medicamentos, y también el riesgo de sufrir interacciones que pueden ser relevantes. Las interacciones más frecuentes son las que afectan a la farmacocinética de los medicamentos y, especialmente, al metabolismo de estos. Aquí el citocromo P450 tiene mucha relevancia, pero desde hace poco más de una década se conoce otro mecanismo implicado, las proteínas transportadoras de membrana. Dentro de estas tienen especial relevancia las OATP (Organic anion transporting polypeptide) de las que existen diferen¬tes tipos y ubicaciones. La competición de diferentes substratos por estas proteínas puede generar interacciones que acaban repercutiendo en el tratamiento farmacoterapeutico del paciente


In the elderly, polymedication is frequent. This increases the risk of adverse reactions to medications, and also the risk of interactions that may be relevant. The most frequent interactions are those that affect the pharmacokinetics of drugs and, especially, their metabolism. Here the cytochrome P450 has a lot of relevance, but for a little more than a decade we know another mechanism involved, the membrane transporter proteins. Within these are the OATP (Organic anion transporting polypeptide) of which there are different types and locations. The competition of different substrates for these proteins can generate interactions that end up having an impact on the pharmacotherapeutic treatment of the patient


Assuntos
Humanos , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética , Olmesartana Medoxomila/efeitos adversos , Olmesartana Medoxomila/farmacocinética , Miosite/induzido quimicamente , Rosuvastatina Cálcica/uso terapêutico , Olmesartana Medoxomila/uso terapêutico
17.
ACS Appl Mater Interfaces ; 10(48): 41012-41018, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30403126

RESUMO

This study explored a new rosuvastatin calcium- and heparin-loaded poly(l-lactide- co-caprolactone) (PLCL) scaffold for covered stents for treating aneurysms. The mechanism of rosuvastatin-induced endothelialization via vascular endothelial growth factor (VEGF)-A elevation was further explored. Rosu50, Rosu75, Rosu100, and phosphate-buffered saline (PBS) nanofibrous scaffolds were fabricated by coaxial electrospinning and observed by electron microscopy. Anticoagulation and pro-endothelialization properties were tested. Sixteen rabbits were selected for an in vivo assay and underwent microsurgery to establish a carotid aneurysm model. The animals were treated with covered stents and followed for 4 months using digital subtraction angiography (DSA), electron microscopy, and histology. Rosuvastatin-treated human umbilical vein endothelial cell (HUVEC) viability, function, and VEGF-A modulation were further studied to elucidate the pro-endothelialization mechanism of rosuvastatin. Our study demonstrates that rosuvastatin and heparin can be incorporated into PLCL nanofibers via electrospinning. Rosu100 nanofiber scaffolds exhibited significant anticoagulation properties. The viability of HUVECs transferred to Rosu100 nanofiber scaffolds was increased significantly. In vivo, DSA revealed that the Rosu100 group had better outcomes than the PBS group. In addition, the Rosu100 stents induced more integrated endothelialization. Further study demonstrated that rosuvastatin promoted HUVEC viability and function in vitro. The effects of rosuvastatin may be attributed to an elevation in VEGF-A. We demonstrated that rosuvastatin- and heparin-loaded PLCL-covered stents show favorable anticoagulation and pro-endothelialization properties in vitro and in vivo in a rabbit aneurysm model. VEGF-A elevation played a crucial role in rosuvastatin-promoted endothelialization. This work provides an additional option for treating cerebral aneurysms with covered stents.


Assuntos
Aneurisma , Artérias Carótidas , Nanofibras/química , Rosuvastatina Cálcica , Stents , Fator A de Crescimento do Endotélio Vascular , Aneurisma/metabolismo , Aneurisma/patologia , Aneurisma/cirurgia , Animais , Caproatos/química , Caproatos/farmacocinética , Caproatos/farmacologia , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Heparina/química , Heparina/farmacocinética , Heparina/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Lactonas/química , Lactonas/farmacocinética , Lactonas/farmacologia , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Coelhos , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/farmacologia , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/farmacocinética , Fator A de Crescimento do Endotélio Vascular/farmacologia
18.
Drug Des Devel Ther ; 12: 3607-3615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464392

RESUMO

Purpose: A new fixed-dose combination (FDC) formulation of 120 mg fimasartan and 20 mg rosuvastatin was developed to increase therapeutic convenience and improve treatment compliance. Methods: A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day washout period was conducted to compare the pharmacokinetic (PK) characteristics and bioequivalence between an FDC of fimasartan/rosuvastatin and the separate co-administration of fimasartan and rosuvastatin in healthy Korean volunteers. The plasma concentrations of fimasartan and rosuvastatin were analyzed by a validated liquid chromatography-tandem mass spectrometry method, for which serial blood samples were collected for up to 48 hours post-administration of fimasartan and 72 hours post-administration of rosuvastatin, in each period. The PK parameters were calculated using a non-compartmental method. Results: A total of 78 subjects completed the study. All the 90% CIs of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. The GMR and 90% CI for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the maximum plasma concentration (Cmax) for fimasartan were 0.9999 (0.9391-1.0646) and 1.0399 (0.8665-1.2479), respectively. The GMR and 90% CI for the AUC0-t and Cmax for rosuvastatin were 1.0075 (0.9468-1.0722) and 1.0856 (0.9944-1.1852), respectively. Treatment with fimasartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion: The new FDC formulation of 120 mg fimasartan and 20 mg rosuvastatin can be substituted for the separate co-administration of fimasartan and rosuvastatin, for the advantage of better compliance with convenient therapeutic administration.


Assuntos
Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , República da Coreia , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/sangue , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Equivalência Terapêutica , Adulto Jovem
20.
Br J Clin Pharmacol ; 84(12): 2877-2888, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171779

RESUMO

AIM: We report on two Phase 1, open-label, single-arm studies assessing the effect of osimertinib on simvastatin (CYP3A substrate) and rosuvastatin (breast cancer resistance protein substrate [BCRP] substrate) exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer who have progressed after treatment with an EGFR tyrosine kinase inhibitor, to determine, upon coadministration, whether osimertinib could affect the exposure of these agents. METHODS: Fifty-two patients in the CYP3A study (pharmacokinetic [PK] analysis, n = 49), and 44 patients in the BCRP study were dosed (PK analysis, n = 44). In the CYP3A study, patients received single doses of simvastatin 40 mg on Days 1 and 31, and osimertinib 80 mg once daily on Days 3-32. In the BCRP study, single doses of rosuvastatin 20 mg were given on Days 1 and 32, and osimertinib 80 mg once daily on Days 4-34. RESULTS: Geometric least squares mean (GLSM) ratios (90% confidence intervals) of simvastatin plus osimertinib for area under the plasma concentration-time curves from zero to infinity (AUC) were 91% (77-108): entirely contained within the predefined no relevant effect limits, and Cmax of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115-157) and Cmax were 172 (146, 203): outside the no relevant effect limits. CONCLUSIONS: Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Rosuvastatina Cálcica/farmacocinética , Sinvastatina/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/fisiologia , Acrilamidas/administração & dosagem , Acrilamidas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Área Sob a Curva , Citocromo P-450 CYP3A/fisiologia , Feminino , Humanos , Hidroxicolesteróis/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/fisiologia
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