RESUMO
Novel methods for peptides structural modification and bioactivity optimization are highly needed in peptide-based drug discovery. Herein, we explored the use gemfibrozil (GFZ) as an albumin binder to enhance the stability and improve the bioactivity of peptides. Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice. Moreover, GFZ endowed 3b with strong lipid-regulating ability in DIO and db/db mice. In a twelve-week study, chronic administration of 3b in db/db mice resulted in sustained glycemic control, to a greater extent than liraglutide and semaglutide. In addition, 3b showed comparable therapeutic efficacies to liraglutide and semaglutide on HbA1c and pancreas islets protection. Our studies reveal 3b as a potential candidate for the treatment of metabolic diseases and indicate dimeric-GFZ modification as a novel method for peptide optimization.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Genfibrozila/química , Peptídeo 1 Semelhante ao Glucagon/química , Hipoglicemiantes/química , Albuminas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Genfibrozila/administração & dosagem , Genfibrozila/farmacocinética , Peptídeos Semelhantes ao Glucagon/farmacologia , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Liraglutida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Xenopus laevisRESUMO
In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Compostos Organofosforados/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico/metabolismo , Área Sob a Curva , Estudos Cross-Over , Indutores do Citocromo P-450 CYP2B6/administração & dosagem , Indutores do Citocromo P-450 CYP2B6/farmacocinética , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Genfibrozila/administração & dosagem , Genfibrozila/farmacocinética , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Rifampina/administração & dosagem , Rifampina/farmacocinéticaRESUMO
AIM: To describe the management of atherogenic dyslipidemia (AD) in routine clinical practice in the Primary Care (PC) setting in Spain. METHODS: Observational, descriptive, cross-sectional study based on a structured questionnaire designed for this study and addressed to PC physicians. The questionnaire content was based on a literature review and was validated by 3 experts in AD. RESULTS: A total of 1029 PC physicians participated in the study. 96.99% indicated that AD is determinant for cardiovascular risk, even if LDL-C levels are appropriate. 88.43% evaluated residual cardiovascular risk in their clinical practice, however, only 27.89% of them evaluated it in secondary prevention. Regarding diagnosis, 82.22% reported that TC, TG, HDL-C and non-HDL-C are essential measures when evaluating AD. Almost all physicians reported that they can request fractionated cholesterol to assess HDL-C and LDL-C, however 3.69% could not. Physicians (95.63%) considered that the first step in AD treatment should be diet, regular exercise, smoking cessation and pharmaceutical treatment, if necessary. 19.1% agreed partially or completely that gemfibrozil is the most suitable fibrate to associate with statins. 74.83% completely agreed that fenofibrate is the most suitable fibrate to combine with statins. CONCLUSIONS: Physicians have access to general Spanish guidelines and recommendations associated with AD management, however, it is necessary to continue rising awareness about the importance of early detection and optimal control of AD to reduce patients' cardiovascular risk.
Assuntos
Aterosclerose/terapia , Dislipidemias/terapia , Médicos de Atenção Primária/estatística & dados numéricos , Atenção Primária à Saúde/métodos , Aterosclerose/diagnóstico , Estudos Transversais , Dislipidemias/diagnóstico , Feminino , Fenofibrato/administração & dosagem , Genfibrozila/administração & dosagem , Pesquisas sobre Atenção à Saúde , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipolipemiantes/administração & dosagem , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde/estatística & dados numéricos , EspanhaRESUMO
PURPOSE: To determine the relationship of illnesses and medical drug consumption with the occurrence of traffic accidents among truck and bus drivers. METHODS: This is a cross-sectional study on truck and bus drivers in Tehran, Iran. The criteria for participating in this study were: married males over 30 years old, driving license in grade one, five years of job experience, mental health and non-addiction license. The criterion for not participating in this study was the lack of cooperation in responding to the questions. Six months was spent to collect the latest five years data of driving accidents from 2011 to 2016. A total of 323 truck and bus drivers in Tehran city and the suburbs, Iran were chosen. Among them, 112 were responsible for accidents (accident group) while 211 were not responsible for any accidents or involved in an accident in the last five years (non-accident group). A specially designed questionnaire was used to investigate the demographic information, medical drug consumption, medical backgrounds and history of accidents. RESULTS: The results revealed that compared with healthy subjects, the occurrence of accidents among people with diabetes (OR = 2.3, p = 0.001) and vision weakness (OR = 1.7, p = 0.020) was significantly higher, while that among people with cardiac (OR = 0.5, p = 0.002) and hypertension (OR = 0.9, p = 0.048) problems was remarkably lower. Moreover, consumption of Gemfibrozil (OR = 1.8, p = 0.010) and Glibenclamide (OR = 2.2, p = 0.002) drugs resulted in significantly higher incidence of accidents than those without. CONCLUSION: Frequencies of illnesses like cardiovascular and hypertension were not higher in accident drivers than in non-accident drivers; but diabetes, vision weakness and consumption of Gemfibrozil and Glibenclamide lead to more traffic accidents.
Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Condução de Veículo/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Adulto , Estudos Transversais , Diabetes Mellitus/epidemiologia , Genfibrozila/administração & dosagem , Glibureto/administração & dosagem , Humanos , Hipolipemiantes/administração & dosagem , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Transtornos da Visão/epidemiologiaRESUMO
Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is associated with Parkinson's disease (PD), upregulation of Nurr1 may be beneficial for PD. However, such mechanisms are poorly understood. This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPARα agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPARα-/-, DA neurons. Moreover, identification of conserved PPRE in the promoter of Nurr1 gene followed by chromatin immunoprecipitation analysis, PPRE luciferase assay, and manipulation of Nurr1 gene by viral transduction of different PPARα plasmids confirmed that PPARα was indeed involved in the expression of Nurr1. Finally, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα-/-, mice identifying PPARα as a novel regulator of Nurr1 expression and associated protection of DA neurons.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , PPAR alfa/metabolismo , Administração Oral , Animais , Sequência de Bases , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Fenofibrato/farmacologia , Genfibrozila/administração & dosagem , Genfibrozila/farmacologia , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Regiões Promotoras Genéticas , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background. OBJECTIVES: The first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners. METHODS: PBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network. RESULTS: The newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI Cmax ratios (Cmax during DDI/Cmax control) are within twofold of the observed values. CONCLUSIONS: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.
Assuntos
Citocromo P-450 CYP2C8/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado/efeitos dos fármacos , Modelos Biológicos , Área Sob a Curva , Carbamatos/administração & dosagem , Carbamatos/farmacocinética , Claritromicina/administração & dosagem , Claritromicina/farmacocinética , Citocromo P-450 CYP2C8/genética , Interações Medicamentosas , Genfibrozila/administração & dosagem , Genfibrozila/farmacocinética , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Pioglitazona/administração & dosagem , Pioglitazona/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Rifampina/administração & dosagem , Rifampina/farmacocinéticaRESUMO
Rhabdomyolysis is characterized by elevation of plasma creatine phosphokinase (CPK) level, and multiple organ disorders, especially renal failure, as well as approximately 50% of acquired rhabdomyolysis are caused by pharmaceuticals. Statins are known to cause rhabdomyolysis, and its incidence is ≥10 times higher with coadministration of statin and fibrate. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by coadministration of statin and fibrate to clarify the mechanisms of its myotoxicity. We administered lovastatin (LV) and gemfibrozil (GF) with a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), to C57BL/6 J female mice once daily for 3 days. The plasma levels of CPK and aspartate aminotransferase (AST) were prominently increased, and the increase in plasma miR-206-3p and miR-133-3p levels, not the increase of miR-122-5p and miR-208-3p levels, suggested skeletal muscle-specific toxicity. The caspase 3/7 activity and mRNA levels of oxidative stress-related factors were elevated in skeletal muscle. Pharmacokinetic parameters showed that blood levels of statin were significantly increased by coadministered GF. The possibility of kidney injury was examined as in clinical rhabdomyolysis. In histological examination, vacuoles were observed in renal proximal tubules, and the plasma renal injury marker, lipocalin 2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal), was markedly increased in the mice coadministered LV and GF, suggesting mild complications of acute kidney injury. A quantitative comparison of the myotoxic potential of various statins was successfully performed using the present method. In this study, a rhabdomyolysis mouse model was established by coadministration of the clinically using statin and fibrate. This mouse model may be useful to identify drugs that have high risk for rhabdomyolysis.
Assuntos
Ácidos Fíbricos/toxicidade , Genfibrozila/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Lovastatina/toxicidade , Rabdomiólise/induzido quimicamente , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Feminino , Ácidos Fíbricos/administração & dosagem , Ácidos Fíbricos/farmacologia , Genfibrozila/administração & dosagem , Genfibrozila/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/administração & dosagem , Lovastatina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Reação em Cadeia da Polimerase em Tempo Real , Rabdomiólise/patologiaRESUMO
Objectives: The study aimed to evaluate the efficacy of combined gemfibrozil with prednisolone in the management of adjuvant-induced arthritis (AIA) rat model. Methods: Seventy two adult male Wistar albino rats were divided equally into 1-control group, three diseased groups: 2- Adjuvant induced arthritis (AIA), 3- high fat diet (HF), and 4- combined AIA-HF, and treated groups: 5- gemfibrozil 30 mg/kg treated AIA group (AIA-G) and the combined AIA-HF treated groups: 6- prednisolone equivalent to human 10 mg (AIA-HF-P10), 7- prednisolone equivalent to human 5 mg (AIA-HF-P5) 8- gemfibrozil (HF-AIA-G) and 9- combined treatment (HF-AIA-G-P5) Results: HF diet represents a precipitating factor for knee arthritis. Gemfibrozil improved the inflammatory findings in both AIA and AIA-HF groups. Combined administration of gemfibrozil with reduced steroid dose gave a similar therapeutic effect to the full steroid dose. Fortunately, we reported more reduction in the nuclear factor kappa-B (NF-κB) and high mobility group box 1 (HMGB1) in the HF-AIA-G-P5 compared with the HF-AIA-P10 group. The improvement was proved by the histological findings. Conclusion: Combined reduced prednisolone dose with gemfibrozil potentiates its anti-inflammatory activity. This could be a target in the management of rheumatoid arthritis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Genfibrozila/uso terapêutico , Prednisolona/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Artrite Experimental/metabolismo , Quimioterapia Combinada , Genfibrozila/administração & dosagem , Humanos , Masculino , NF-kappa B/metabolismo , PPAR alfa/agonistas , Prednisolona/administração & dosagem , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Previous pre-clinical studies demonstrated a promising role of alpha-type peroxisome proliferator-activated receptors (PPARα) agonists in decreasing nicotine self-administration and nicotine-seeking behavior in animals. Our goal was to investigate the potential of gemfibrozil, a PPARα agonist, on reducing tobacco smoking in humans. METHODS: This was a double-blind, placebo-controlled, crossover study evaluating the effects of gemfibrozil (1200 mg/day) on smoking in 27 treatment-seeking smokers. The study had two 2-week phases separated by a washout period of at least 1 week. In each phase and after 1 week on medication, participants underwent a lab session where cue reactivity and forced choice paradigms were conducted. Physiological responses and self-reported craving were monitored during the presentation of smoking and neutral cues. In addition, two types of cigarettes were used in the forced choice paradigms: the Nicotinized cigarettes (Nic) and the Denicotinized cigarettes (Denic). The goal of the forced choice was to calculate the percentage of choice of Nic cigarettes while taking gemfibrozil or placebo. The number of quit days was calculated during the two quit attempts weeks (one while taking gemfibrozil and one while taking placebo) of the study. RESULTS: There were no significant differences between gemfibrozil and placebo groups in the percentage of choice of Nic cigarettes, the cue-reactivity (both physiological and subjective measures), or in the number of days of abstinence. CONCLUSIONS: Although preclinical studies with PPAR α agonists showed promising results, this preliminary study did not demonstrate positive effect of gemfibrozil on tobacco use and cessation indices.
Assuntos
Genfibrozila/administração & dosagem , PPAR alfa/agonistas , Agentes de Cessação do Hábito de Fumar/administração & dosagem , Abandono do Hábito de Fumar , Fumar/tratamento farmacológico , Adulto , Estudos Transversais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The therapeutic management of severe hypertriglyceridaemia represents a clinical challenge. OBJECTIVES: The objectives of this study were 1) to identify the clinical characteristics of patients with severe hypertriglyceridaemia, and 2) to analyse the treatment established by the physicians in each case. METHODS: A cross-sectional study was carried out using the computerised medical records of all patients>18 years of age with a blood triglyceride level≥1,000mg/dL between 1 January 2011 and 31 December 2016. Clinical and laboratory variables were collected. The behaviour of the physicians in the 6 months after the lipid finding was analysed. RESULTS: A total of 420 patients were included (mean age 49.1±11.4 years, males 78.8%). The median of triglycerides was 1,329mg/dL (interquartile range 1,174-1,658). No secondary causes were found in 34.1% of the patients. The most frequent secondary causes were obesity (38.6%) and diabetes (28.1%). Physical activity was recommended and a nutritionist was referred to in 49.1% and 44.2% of the patients, respectively. Secondary causes were identified and attempts were made to correct them in 40.7% of cases. The most indicated pharmacological treatments were fenofibrate 200mg/day (26.5%) and gemfibrozil 900mg/day (19.3%). Few patients received the indication of omega 3 fatty acids or niacin. CONCLUSION: This study showed, for the first time in our country, the characteristics of a population with severe hypertriglyceridaemia. The therapeutic measures instituted by the physicians were insufficient. Knowing the characteristics in this particular clinical scenario could improve the current approach of these patients.
Assuntos
Hipertrigliceridemia/terapia , Hipolipemiantes/administração & dosagem , Lipídeos/sangue , Triglicerídeos/sangue , Adulto , Estudos Transversais , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Fenofibrato/administração & dosagem , Genfibrozila/administração & dosagem , Humanos , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Niacina/administração & dosagem , Padrões de Prática Médica/normas , Índice de Gravidade de DoençaRESUMO
AIMS: Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. METHODS: The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. RESULTS: Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-∞ by half (90% CI 0.45, 0.59). CONCLUSION: Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged.
Assuntos
Acetamidas/farmacocinética , Acetatos/farmacocinética , Anti-Hipertensivos/farmacocinética , Indutores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Genfibrozila/administração & dosagem , Pró-Fármacos/farmacocinética , Pirazinas/farmacocinética , Rifampina/administração & dosagem , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Acetamidas/sangue , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/sangue , Ativação Metabólica , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C8/metabolismo , Indutores do Citocromo P-450 CYP2C8/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Interações Medicamentosas , Genfibrozila/efeitos adversos , Alemanha , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/sangue , Rifampina/efeitos adversos , Medição de Risco , Adulto JovemRESUMO
Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates.
Assuntos
Inibidores do Citocromo P-450 CYP2C8/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Genfibrozila/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , Animais , Citocromo P-450 CYP2B1/química , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/genética , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Genfibrozila/administração & dosagem , Hipolipemiantes/administração & dosagem , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/metabolismoRESUMO
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (Ki ) â¼1.1 and 0.014 µM, respectively) and OATP1B3 (Ki â¼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; Ki â¼0.07 µM). The predicted effects of gemfibrozil and its metabolite were moderate (1.88-fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter-mediated DDIs with novel pharmaceutical agents in development.
Assuntos
Ciclosporina/administração & dosagem , Genfibrozila/administração & dosagem , Rifampina/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Intravenosa , Administração Oral , Área Sob a Curva , Ciclosporina/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Genfibrozila/farmacocinética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Modelos Teóricos , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Rifampina/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de SolutoRESUMO
A rapid and sensitive bioassay was established and validated to simultaneously determine gemfibrozil, morphine, morphine-3ß-glucuronide, and morphine-6ß-glucuronide in mouse cerebrum, epencephalon, and hippocampus based on ultra-high performance liquid chromatography and tandem mass spectrometry. The deuterated internal standard, M6G-d3, was mixed with the prepared samples at 10 ng/mL as the final concentration. The samples were transferred into the C18 solid-phase extraction columns with gradient elution for solid-phase extraction. The mobile phase consisted of methanol and 0.05% formic acid (pH 3.2). Multiple reaction monitoring has been applied to analyze gemfibrozil (m/z 249.0 â 121.0) in anion mode, and M6G-d3 (m/z 465.1 â 289.1), morphine (m/z 286.0 â 200.9), and M3G and M6G (m/z 462.1 â 286.1) in the positive ion mode. The method has a linear calibration range from 0.05 to 10 ng for gemfibrozil, morphine, and M3G and M6G with correlation coefficients >0.993. The lower limit of quantitation for all four analytes was 0.05 ng/mL, relative standard deviation of intra- and interday precision was less than 10.5%, and the relative error of accuracy was from -8.2 to 8.3% at low, medium, and high concentrations for all the analytes. In conclusion, gemfibrozil can influence the morphine antinociception after coronary heart disease induced chronic angina by the change in one of morphine metabolites', M3G, distribution in mouse brain.
Assuntos
Encéfalo/metabolismo , Genfibrozila/análise , Morfina/análise , Extração em Fase Sólida , Animais , Cromatografia Líquida de Alta Pressão , Genfibrozila/administração & dosagem , Genfibrozila/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Morfina/administração & dosagem , Morfina/metabolismo , Espectrometria de Massas em TandemRESUMO
Elevated concentration of any or all types of lipids in the plasma including hypertriglyceridemia and hypercholesterolemia leads to atherosclerotic cardiovascular disease. Effective medication needs multiple drug therapy as recommended cholesterol and triglyceride levels are difficult to achieve by monotherapy and frequently require the use of more than one lipid-lowering medication. Gemfibrozil lowers plasma triglyceride-rich lipoproteins mainly VLDL and increases HDL. It is associated with short plasma half-life (1.5h) and GIT distress on long term use. In a study it was found that ethanolamine decreases serum cholesterol, especially VLDL cholesterol and LDL cholesterol in rats fed an HF/HC diet. In the present work, we thought of exploring the effect of co-drug of gemfibrozil with ethanolamine (GE-I) as a potential combination therapy for the management of mixed hyperlipidemia. Synthesis of GE-I was effected by CDI coupling. Structure was confirmed spectrally. Interestingly kinetic studies revealed that GE-I resisted chemical and enzymatic hydrolysis. In tritoninduced hyperlipidemia, significant lowering of serum lipid levels was observed. The hallmark of GEI was its profound effect on HDL level which was raised above the normal level by 15%. Docking study also supported modulatory effect of GE-I (docking score -7.012) on PPAR-α which was comparable to docking score of gemfibrozil (-9.432). These preliminary observations prompt us to consider GE-I as a novel, serendipitous, hybrid anti-hyperlipidemic new chemical entity which needs be studied extensively to prove it as an HDL enhancing anti-hyperlipidemic agent.
Assuntos
HDL-Colesterol/efeitos dos fármacos , Etanolamina/farmacologia , Genfibrozila/farmacologia , Hiperlipidemias/tratamento farmacológico , Amidas/química , Animais , HDL-Colesterol/metabolismo , Modelos Animais de Doenças , Etanolamina/administração & dosagem , Etanolamina/química , Genfibrozila/administração & dosagem , Genfibrozila/química , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Masculino , Simulação de Acoplamento Molecular , Octoxinol/toxicidade , PPAR alfa/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Little is known about the use and effectiveness of over-the-counter (OTC) fish oil supplements for triglyceride (TG) lowering. OBJECTIVES: To (1) perform a medication-use evaluation (MUE) and (2) assess the efficacy of OTC fish oil. METHODS: Retrospective, observational cohort study using electronic medical records and the pharmacy database from Parkland Health and Hospital System in Dallas, Texas. Parkland is a tax-supported county institution that provides patients with single-brand OTC fish oil. Two separate analyses were conducted. Six hundred seventeen patients (prescribed fish oil between July 1, 2012, and August 31, 2012) were included in the MUE analysis and 235 patients (109 fish oil, 72 fenofibrate, and 54 gemfibrozil, prescribed between January 1, 2012, and July 31, 2013) were included in the efficacy analysis. The main outcome measure for the MUE was fish oil prescribing habits including dosages and patient adherence, as defined by medication possession ratio. The main outcome measure for the efficacy analysis was change in lipids measured using the last value before fish oil treatment and the first value after fish oil treatment. RESULTS: MUE: 617 patients received prescriptions for OTC fish oil. Sixty-four percent were prescribed a total daily dose of 2000 mg. Only 25% of patients were adherent. Efficacy analysis: despite being prescribed suboptimal doses, fish oil reduced TGs by 29% (95% confidence interval, 34.3-22.7). Compared with fish oil therapy, fibrate therapy resulted in a greater TG reduction: 48.5% (55.1-41.0) with fenofibrate and 49.8% (57.6-40.5) with gemfibrozil (P < .0001, both medications compared with fish oil). CONCLUSIONS: Health care providers prescribe suboptimal doses of fish oil, and adherence is poor. Even at low doses (2 g/d), though, fish oil lowers TGs by 29%.
Assuntos
Óleos de Peixe/administração & dosagem , Hipolipemiantes/administração & dosagem , Medicamentos sem Prescrição/administração & dosagem , Triglicerídeos/sangue , Adulto , Idoso , Feminino , Fenofibrato/administração & dosagem , Genfibrozila/administração & dosagem , Hospitais Públicos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In recent years, Solea senegalensis has increasingly been used in pollution monitoring studies. In order to assess its response to some particular widespread pollutants, juveniles of S. senegalensis were administered an intraperitoneal injection of the model aryl hydrocarbon receptor agonist ß-naphtoflavone (ßNF) and chemicals of environmental concern, such as the fungicide ketoconazole (KETO), the lipid regulator gemfibrozil (GEM), the surfactant nonylphenol (NP) and the synthetic hormone ethinylestradiol (EE2). Two days after injection, the effect of these chemicals was followed up as alterations of hepatic microsomal activities of the cytochrome P450 (CYPs) and associated reductases, carboxylesterases (CbEs) and the conjugation enzyme uridine diphosphate glucuronyltransferase (UDPGT). In the cytosolic fraction of the liver, the effect on CbEs, glutathione S-transferase (GST) and antioxidant activities was also considered. Alterations on the endocrine reproductive system were evaluated by plasma levels of vitellogenin (VTG) and the sex steroids estradiol (E2), testosterone (T), 11-ketotestosterone (11KT) and the progestin 17α,20ß-dihydroxy-4-pregnen-3-one (17,20ß-P). Injection with the model compound ßNF induced the hydrolysis rate of the seven CYP substrates assayed. The xenobiotic GEM induced three CYP-related activities (e.g. ECOD) and UDPGT, but depressed antioxidant defenses. EE2 induced four CYPs, more significantly ECOD and BFCOD activities. The xenoestrogens NP and EE2 altered the activities of CbE in microsomes and catalase, and were the only treatments that induced de novo VTG synthesis. In addition, the progestin 17,20ß-P, was induced in NP-injected fish. None of the treatments caused statistically significant effects on steroid plasma levels. In conclusion, the CYP substrates assayed responded specifically to treatments and juveniles of S. senegalensis appear good candidates for assessing xenobiotics exposure.
Assuntos
Biomarcadores/metabolismo , Linguados/sangue , Xenobióticos/metabolismo , Xenobióticos/farmacologia , Animais , Biomarcadores/sangue , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacologia , Flavonas/administração & dosagem , Flavonas/farmacologia , Genfibrozila/administração & dosagem , Genfibrozila/farmacologia , Hormônios Esteroides Gonadais/sangue , Hidrólise/efeitos dos fármacos , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Fenóis/administração & dosagem , Fenóis/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Estatísticas não Paramétricas , Vitelogeninas/sangue , Xenobióticos/administração & dosagemRESUMO
Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia-reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.
Assuntos
Anti-Inflamatórios/toxicidade , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Genfibrozila/toxicidade , Genfibrozila/uso terapêutico , Degeneração Neural/induzido quimicamente , Proteínas do Tecido Nervoso/biossíntese , Fármacos Neuroprotetores/toxicidade , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Feminino , Genfibrozila/administração & dosagem , Genfibrozila/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/análise , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/fisiologia , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Pré-Medicação , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
PURPOSE: To develop physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and drug-drug interactions (DDI) of pravastatin, using the in vitro transport parameters. METHODS: In vitro hepatic sinusoidal active uptake, passive diffusion and canalicular efflux intrinsic clearance values were determined using sandwich-culture human hepatocytes (SCHH) model. PBPK modeling and simulations were implemented in Simcyp (Sheffield, UK). DDI with OATP1B1 inhibitors, cyclosporine, gemfibrozil and rifampin, was also simulated using inhibition constant (Ki) values. RESULTS: SCHH studies suggested active uptake, passive diffusion and efflux intrinsic clearance values of 1.9, 0.5 and 1.2 µL/min/10(6)cells, respectively, for pravastatin. PBPK model developed, using transport kinetics and scaling factors, adequately described pravastatin oral plasma concentration-time profiles at different doses (within 20% error). Model based prediction of DDIs with gemfibrozil and rifampin was similar to that observed. However, pravastatin-cyclosporine DDI was underpredicted (AUC ratio 4.4 Vs ~10). Static (R-value) model predicted higher magnitude of DDI compared to the AUC ratio predicted by the PBPK modeling. CONCLUSIONS: PBPK model of pravastatin, based on in vitro transport parameters and scaling factors, was developed. The approach described can be used to predict the pharmacokinetics and DDIs associated with hepatic uptake transporters.
Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , Pravastatina/farmacologia , Pravastatina/farmacocinética , Adolescente , Adulto , Idoso , Área Sob a Curva , Transporte Biológico , Células Cultivadas , Simulação por Computador , Ciclosporina/administração & dosagem , Ciclosporina/farmacocinética , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Genfibrozila/administração & dosagem , Genfibrozila/farmacocinética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Pravastatina/administração & dosagem , Rifampina/administração & dosagem , Rifampina/farmacocinética , Adulto JovemRESUMO
STUDY OBJECTIVE: To describe the prevalence of prescribing against-label statin-fibrate combination therapy. DESIGN: Retrospective cohort study. DATA SOURCE: Medstat MarketScan Commercial Claims and Encounter database. PATIENTS: Adults (aged 18-89 yrs) who were prescribed statin-fibrate combination therapy between January 1, 2003, and June 30, 2009, had pharmacy claims demonstrating two or more concurrently filled prescriptions for a statin and a fibrate, and had continuous insurance enrollment for at least 12 months. MEASUREMENTS AND MAIN RESULTS: Claims data were used to identify patients with dyslipidemia based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. National Drug Codes were used to describe concurrent statin-fibrate combination therapy. The primary outcome was recent use of against-label statin-fibrate combination therapy, defined as use during the last 18 months (January 1, 2008-June 30, 2009) of the study period. Patients were stratified according to statin and dosage to identify against-label combination use (e.g., simvastatin > 10 mg/day with gemfibrozil). Within the recent-use period, 131,394 patients were prescribed concurrent statin-fibrate combination therapy; of these patients, 13,420 (10.2%) had against-label therapy. Simvastatin-gemfibrozil accounted for 8978 (66.9%) of all against-label combinations. Of all 9877 simvastatin-gemfibrozil combinations prescribed in the recent-use period (both on-label and against-label use), 8978 (90.9%) were against label. The secondary outcome was prevalence of against-label statin-fibrate combination therapy on an annual basis: 15.5% in 2003, 18.7% in 2004, 9.1% in 2005, 8.3% in 2006, 9.2% in 2007, and 9.8% in 2008. CONCLUSION: Against-label statin-fibrate combination therapy continues to be prescribed despite established United States Food and Drug Administration (FDA) dose restrictions. Nearly every time the simvastatin-gemfibrozil combination was prescribed, it was against label because simvastatin exceeded the maximum dose restriction. Updated simvastatin labeling in June 2011 includes additional maximum dose restrictions and new contraindications, which include gemfibrozil. Different approaches in clinical practice are needed to ensure adherence with the revised FDA labeling.