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Medicinas Complementárias
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1.
Pharm Biol ; 60(1): 359-373, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35171063

RESUMEN

CONTEXT: Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. OBJECTIVE: The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. MATERIALS AND METHODS: The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. RESULTS: Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 µg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC0-∞ (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1ß, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. DISCUSSION AND CONCLUSIONS: Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Transportadores de Anión Orgánico/genética , Pravastatina/farmacocinética , Quinazolinas/farmacología , Animales , Área Bajo la Curva , Interacciones de Hierba-Droga , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos
2.
Pharm Biol ; 60(1): 185-194, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35001796

RESUMEN

CONTEXT: Atorvastatin (ATV) and QiShenYiQi pills (QSYQ), a Chinese patent medicine, are often co-prescribed to Chinese cardiovascular patients. The effects of QSYQ on the pharmacokinetics of ATV have not been studied. OBJECTIVE: We investigated the influence of QSYQ on the pharmacokinetics of ATV and its metabolites upon oral or intravenous administration of ATV to rats. MATERIALS AND METHODS: Sprague-Dawley rats (n = 5/group) were pre-treated with oral QSYQ (675 mg/kg) or vehicle control for 7 days and then orally administrated ATV (10 mg/kg) or intravenously administrated ATV (2 mg/kg). Serum concentrations of ATV and metabolites were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Expression of metabolic enzymes and transporters in jejunum and ileum were measured by quantitative real-time PCR and Western blot. RESULTS: QSYQ resulted in an increase of AUC0-12 h of ATV from 226.67 ± 42.11 to 408.70 ± 161.75 ng/mL/h and of Cmax of ATV from 101.46 ± 26.18 to 198.00 ± 51.69 ng/mL and in an increased of para-hydroxy atorvastatin from 9.07 ± 6.20 to 23.10 ± 8.70 ng/mL in rats administered ATV orally. No change was observed in rats treated intravenously. The expression of multidrug resistance-associated protein 2 mRNA and protein decreased in ileum, and the mRNA of P-glycoprotein decreased in jejunum, though no change in protein expression was found. DISCUSSION AND CONCLUSIONS: QSYQ increased bioavailability of ATV administered orally through inhibiting the expression of Mrp2 in ileum. Clinicians should pay close attention to potential drug-drug interactions between ATV and QSYQ.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Atorvastatina/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Interacciones de Hierba-Droga , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Íleon/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem
3.
Eur J Drug Metab Pharmacokinet ; 47(1): 117-126, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34855161

RESUMEN

BACKGROUND AND OBJECTIVES: Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly atrovastatin calcium) in TCM clinics. However, the herb-drug interaction between GQD and atrovastatin calcium (AC) is still unknown. To determine whether the combination is safe, we evaluated the effects of GQD on the activities of cytochrome P450 (CYP) 3A2 enzyme and investigated the impact of GQD on the pharmacokinetics and pharmacodynamics of AC in rats. METHODS: The pharmacokinetics of AC (10 mg/kg) with or without pretreatment with GQD (freeze-dried powder, 1.35 g/kg) were investigated using HPLC. The influence of GQD on pharmacodynamics of AC were determined by detecting the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, the probe drug method was used to explore the effect of GQD on CYP3A2 activity. RESULTS: The pharmacokinetic parameters of AC combined with GQD were significantly affected (P < 0.05) in hyperlipidemic rats. The serum TC, TG and LDL-C levels of the combination were significantly reduced (P < 0.05), and the serum HDL-C level was significantly increased (P < 0.05) compared with AC/GQD alone. AST and ALT activities treated with both GQD and AC+GQD group were significantly reduced (P < 0.05) compared with AC group. There was a significant difference in the pharmacokinetic parameters of midazolam between control and GQD groups (P < 0.05). Maximum concentration (Cmax), area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) increased significantly in GQD group. CONCLUSIONS: The result suggested that GQD combined with AC can improve the lipid-lowering effect of AC and reduce the damage of AC to the liver simultaneously. However, GQD can inhibit the activity of CYP3A2 in hyperlipidemic rats and increase the blood concentration of AC. Therefore, the clinical dose of AC should be adjusted when they are combined. Since the study was conducted in rats,  further research should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.


Asunto(s)
Atorvastatina/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Animales , Área Bajo la Curva , Atorvastatina/sangre , Modelos Animales de Enfermedad , Interacciones de Hierba-Droga , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Hiperlipidemias/tratamiento farmacológico , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
4.
J Ethnopharmacol ; 280: 114469, 2021 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-34329714

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. is a traditional Chinese medicine for hyper lipaemia. Ginkgo flavonols and terpene lactones are responsible for the lipid-lowering effect in non-alcoholic fatty liver disease (NAFLD). However, the pharmacokinetics of ginkgo flavonols and terpene lactones in NAFLD was not clarified. AIM OF THE STUDY: To investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats. MATERIALS AND METHODS: Male rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of 3H-ES were tested in hOATP1B1-HEK293 cells. RESULTS: The plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6-32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2-3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the Cmax and AUC0-t of pitavastatin by 1.8-3.2 and 1.3-3.0 folds, respectively. In hOATP1B1-HEK293 cells, kaempferol and isorhamnetin contributed to the inhibition of OATP1B1-mediated uptake of 3H-ES with IC50 values of 3.28 ± 1.08 µM and 46.12 ± 5.25 µM, respectively. CONCLUSIONS: NAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Extractos Vegetales/farmacología , Quinolinas/farmacocinética , Animales , Área Bajo la Curva , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ginkgo biloba , Células HEK293 , Interacciones de Hierba-Droga , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo
5.
Drug Metab Dispos ; 49(9): 780-789, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34330719

RESUMEN

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study, we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion, and plasma exposure of drugs. For this evaluation, we dosed atorvastatin, pitavastatin, and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDIs) on these processes. After 120 minutes of perfusion, 0.104 mg atorvastatin (n = 3), 0.140 mg pitavastatin (n = 5), or 1.4 mg rosuvastatin (n = 4) was administered to the portal vein, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human-specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank order of the DDI between the various systems upon coadministration with rifampicin could be observed: atorvastatin (AUC ratio 7.2) > rosuvastatin (AUC ratio 3.1) > pitavastatin (AUC ratio 2.6), which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion, and plasma profile of drugs. SIGNIFICANCE STATEMENT: This study evaluated the use of normothermic machine perfusion (NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins, and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.


Asunto(s)
Interacciones Farmacológicas , Eliminación Hepatobiliar/fisiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inactivación Metabólica/fisiología , Hígado , Animales , Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Diseño de Equipo , Técnicas In Vitro/instrumentación , Hígado/metabolismo , Hígado/patología , Tasa de Depuración Metabólica , Perfusión/instrumentación , Perfusión/métodos , Reproducibilidad de los Resultados , Porcinos
6.
AAPS J ; 22(6): 133, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33063163

RESUMEN

Suspended human hepatocytes (SHH) have long been used in assessing hepatic drug uptake, while plated human hepatocytes in short-term monolayer culture (PHH) have gained use in recent years. This study aimed to cross-evaluate SHH and PHH in measuring the hepatic uptake mediated by organic anion transporting polypeptide 1Bs (OATP1Bs). We compared the time courses of cell-to-medium (C/M) concentration ratios and initial uptake clearance values of the OATP1B substrates (pitavastatin, rosuvastatin, cerivastatin, pravastatin, dehydropravastatin, and SC-62807) between SHH and PHH. For all compounds except cerivastatin, the C/M ratios in SHH displayed an apparent overshoot (an initial increase followed by a decrease) during the 180-min uptake experiment, but not in PHH. Based on the literature evidence suggesting the possible internalization of OATP1Bs in primary hepatocytes, separate experiments measured the drug uptake after varying lengths of pre-incubation in the drug-free medium. The initial uptake clearances of pitavastatin and rosuvastatin declined in SHH beyond an apparent threshold time of 20-min drug-free pre-incubation, but not in PHH. Kinetic modeling quantitatively captured the decline in the active uptake clearance in SHH, and more than half of the active uptake clearances of pitavastatin and rosuvastatin were prone to loss during the 180-min uptake experiment. These results suggested a partial, time-delayed loss of the functional OATP1Bs in SHH upon prolonged incubation. Our results indicate that PHH is more appropriate for experiments where a prolonged incubation is required, such as estimation of unbound hepatocyte-to-medium concentration ratio (Kp,uu) at the steady-state.


Asunto(s)
Hepatocitos/enzimología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Adulto , Células Cultivadas , Niño , Medios de Cultivo/análisis , Medios de Cultivo/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Eliminación Hepatobiliar , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/análisis , Masculino , Modelos Biológicos , Cultivo Primario de Células/métodos
7.
J Cell Mol Med ; 24(18): 11024-11029, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32767644

RESUMEN

The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High-fat diet-fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti-hypercholesterolaemia and anti-hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non-esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid-lowering effects of simvastatin.


Asunto(s)
Péptidos y Proteínas de Señalización del Ritmo Circadiano/fisiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Hiperlipidemias/tratamiento farmacológico , Simvastatina/farmacocinética , Animales , Cronofarmacocinética , Relojes Circadianos/efectos de los fármacos , Péptidos y Proteínas de Señalización del Ritmo Circadiano/biosíntesis , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Dieta Alta en Grasa/efectos adversos , Cronoterapia de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Obesos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Distribución Aleatoria , Simvastatina/administración & dosificación , Simvastatina/uso terapéutico
8.
Drug Metab Dispos ; 48(9): 750-758, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32616544

RESUMEN

Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT: Static model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.


Asunto(s)
Interacciones Farmacológicas , Eliminación Hepatobiliar/fisiología , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Modelos Biológicos , Área Bajo la Curva , Ciclosporina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Células HEK293 , Eliminación Hepatobiliar/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Concentración 50 Inhibidora , Isoquinolinas/farmacología , Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Rosuvastatina Cálcica/farmacocinética , Sulfonamidas/farmacología
9.
Clin Pharmacol Ther ; 108(2): 287-297, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32128760

RESUMEN

Atorvastatin (ATV) is frequently prescribed and generally well  tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV.


Asunto(s)
Atorvastatina/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Atorvastatina/efectos adversos , Atorvastatina/análogos & derivados , Atorvastatina/farmacocinética , Biotransformación , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Lactonas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/genética , Farmacogenética , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Reino Unido
10.
Eur J Drug Metab Pharmacokinet ; 45(3): 351-360, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31997084

RESUMEN

BACKGROUND AND OBJECTIVES: Green tea catechins were recently reported to inhibit drug transporters such as organic anion-transporting polypeptides (OATPs) and metabolic enzymes, affecting the bioavailability of many drugs. This study aimed to evaluate the clinical significance of the effects of different doses of green tea extract on the pharmacokinetic parameters of atorvastatin and to rationalize the associated interaction mechanism. METHODS: A randomized, double-blind, three-phase crossover study involving 12 healthy volunteers was performed. Participants received a single dose of atorvastatin 40 mg alone (control group), atorvastatin 40 mg plus a capsule containing 300 mg of dry green tea extract, or atorvastatin 40 mg plus a capsule containing 600 mg of dry green tea extract. Plasma samples taken from the volunteers were analyzed for atorvastatin using liquid chromatography-tandom mass spectrometry (LC/MS/MS). RESULTS: Compared to atorvastatin alone, the administration of 300 mg or 600 mg of the green tea extract along with atorvastatin decreased the peak plasma concentration (Cmax) of atorvastatin by 25% and 24%, respectively (P < 0.05), and the area under the plasma concentration-time curve (AUC0-∞) of atorvastatin by 24% and 22%, respectively (P < 0.05). Additionally, administration of 300 mg or 600 mg of the green tea extract increased the apparent oral clearance (CL/F) of atorvastatin by 31% and 29%, respectively. The time to Cmax (Tmax) and the elimination half-life (t1/2) of atorvastatin did not differ among the three phases. The effects of 600 mg of the green tea extract on the pharmacokinetic parameters of atorvastatin were not significantly different from the effects of 300 mg of the green tea extract. CONCLUSION: Green tea extract decreases the absorption but not the elimination of atorvastatin, possibly by inhibiting OATP, albeit not in a dose-dependent manner. Coadministration of green tea extract with atorvastatin may necessitate the monitoring of the plasma concentration of atorvastatin in clinical practice.


Asunto(s)
Atorvastatina/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Extractos Vegetales/farmacología , Té/química , Adulto , Área Bajo la Curva , Catequina/farmacología , Cromatografía Liquida , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones de Hierba-Droga , Humanos , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/antagonistas & inhibidores , Extractos Vegetales/administración & dosificación , Espectrometría de Masas en Tándem , Adulto Joven
11.
J Med Chem ; 61(8): 3609-3625, 2018 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-29634260

RESUMEN

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.


Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Terpenos/uso terapéutico , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/toxicidad , Estabilidad de Medicamentos , Hígado Graso/tratamiento farmacológico , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/farmacocinética , Inhibidores de Glicósido Hidrolasas/toxicidad , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/toxicidad , Lactonas/síntesis química , Lactonas/farmacocinética , Lactonas/uso terapéutico , Lactonas/toxicidad , Masculino , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Ratas Sprague-Dawley , Porcinos , Terpenos/síntesis química , Terpenos/farmacocinética , Terpenos/toxicidad , alfa-Glucosidasas/metabolismo
12.
Pharm Biol ; 56(1): 104-108, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29322864

RESUMEN

CONTEXT: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic. OBJECTIVE: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of AC (1 mg/kg) with or without pretreatment of DST (100 mg/kg) were investigated using LC-MS/MS. The effects of DST (50 µg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems. RESULTS: The results indicated that Cmax (23.87 ± 4.27 vs. 38.94 ± 5.32 ng/mL), AUC(0-t) (41.01 ± 11.32 vs. 77.28 ± 12.92 ng h/mL), and t1/2 (1.91 ± 0.18 vs. 2.74 ± 0.23 h) decreased significantly (p < 0.05) when DST and AC were co-administered, which suggested that DST might influence the pharmacokinetic behavior of AC when they are co-administered. The metabolic stability (t1/2) of AC was also decreased (25.7 ± 5.2 vs. 42.5 ± 6.1) with the pretreatment of DST. DISCUSSION AND CONCLUSIONS: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered.


Asunto(s)
Atorvastatina/farmacocinética , Medicamentos Herbarios Chinos/farmacocinética , Interacciones de Hierba-Droga/fisiología , Microsomas Hepáticos/efectos de los fármacos , Salvia miltiorrhiza , Animales , Atorvastatina/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley
13.
Eur J Clin Pharmacol ; 74(5): 601-609, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29368187

RESUMEN

PURPOSE: The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers. METHODS: The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer. RESULTS: EGCG inhibited diclofenac 4'-hydroxylation and fluvastatin degradation with IC50 of 2.23 and 48.04 µM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration-time curve (AUC0-∞) of fluvastatin were 0.993 (0.963-1.024, vs. brewed green tea) and 0.977 (0.935-1.020, vs. GTE). CONCLUSIONS: Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.


Asunto(s)
Catequina/análogos & derivados , Citocromo P-450 CYP2C9/metabolismo , Ácidos Grasos Monoinsaturados/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Indoles/farmacocinética , , Adulto , Antiinflamatorios no Esteroideos/farmacocinética , Catequina/análisis , Catequina/sangre , Catequina/farmacocinética , Catequina/farmacología , Estudios Cruzados , Diclofenaco/farmacocinética , Ácidos Grasos Monoinsaturados/sangre , Femenino , Fluvastatina , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Indoles/sangre , Masculino , Té/química , Adulto Joven
14.
Biochem Pharmacol ; 142: 216-228, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28636885

RESUMEN

The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Artritis Experimental/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Expresión Génica , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Transportadores de Anión Orgánico/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Administración Oral , Animales , Área Bajo la Curva , Artritis Experimental/inducido químicamente , Artritis Experimental/inmunología , Colágeno/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Relación Dosis-Respuesta a Droga , Femenino , Hepatocitos/enzimología , Hepatocitos/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Inyecciones Intravenosas , Mucosa Intestinal/metabolismo , Intestinos/enzimología , Tasa de Depuración Metabólica , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Transportadores de Anión Orgánico/genética , Ratas Endogámicas Lew , Distribución Tisular
15.
Drug Des Devel Ther ; 11: 1409-1416, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28533679

RESUMEN

Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration-time curve from time 0 to the last measurable time (AUClast) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67-0.97) and the peak plasma concentration (Cmax) by 15% (geometric mean ratio 0.85, 90% CI 0.70-1.04). AUClast or Cmax of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG.


Asunto(s)
Catequina/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Té/química , Adulto , Área Bajo la Curva , Catequina/aislamiento & purificación , Catequina/farmacología , Femenino , Interacciones de Hierba-Droga , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Rosuvastatina Cálcica/administración & dosificación , Adulto Joven
16.
Pharmacol Ther ; 175: 1-16, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28223230

RESUMEN

Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D3.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Animales , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Células Musculares/metabolismo , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/fisiopatología , Enfermedades Musculares/prevención & control
17.
J Pharm Sci ; 106(5): 1439-1451, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28089685

RESUMEN

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.


Asunto(s)
Aminobutiratos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Modelos Biológicos , Tetrazoles/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Compuestos de Bifenilo , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas/fisiología , Humanos , Valsartán
18.
Curr Drug Metab ; 17(9): 877-896, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27654899

RESUMEN

Statins are cholesterol-lowering agents which belong to the group of the most commonly prescribed drugs. The use of statins has become the standard treatment in patients with an increased risk of cardiovascular and coronary heart diseases. However, many clinical studies have shown that 13 - 75% of patients fail to achieve LDL-cholesterol and total cholesterol target levels. The clinical implications of insufficient response include cardiovascular complications caused by atherosclerosis leading to acute myocardial infarction, stroke and death. The mechanism underlying statin resistance has been associated with genetic polymorphisms and nongenetic factors (e.g. concomitant diseases, drug-drug interactions, interactions with food and dietary supplements). The article provides a comprehensive update of the current knowledge regarding the role of genetic polymorphism and non-genetic determinants of cholesterol-lowering effect of statins. Dietary aspects of statin efficacy were also presented. The Pubmed search was performed to identify relevant papers from the last ten years which were included in the review. Consideration of the genetic and non-genetic determinants of pharmacological action of statins as well as mechanisms of drug-drug interactions may be useful in clinical practice for improving safety and efficacy of statin treatment.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Colesterol/sangre , Comorbilidad , Suplementos Dietéticos , Interacciones Farmacológicas , Alimentos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Variantes Farmacogenómicas
19.
Adv Clin Chem ; 73: 127-68, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26975972

RESUMEN

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Elevated blood lipids may be a major risk factor for CVD. Due to consistent and robust association of higher low-density lipoprotein (LDL)-cholesterol levels with CVD across experimental and epidemiologic studies, therapeutic strategies to decrease risk have focused on LDL-cholesterol reduction as the primary goal. Current medication options for lipid-lowering therapy include statins, bile acid sequestrants, a cholesterol-absorption inhibitor, fibrates, nicotinic acid, and omega-3 fatty acids, which all have various mechanisms of action and pharmacokinetic properties. The most widely prescribed lipid-lowering agents are the HMG-CoA reductase inhibitors, or statins. Since their introduction in the 1980s, statins have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes (Kapur and Musunuru, 2008 [1]). The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia. This chapter focuses on the biochemistry of statins including their structures, pharmacokinetics, and mechanism of actions as well as the potential adverse reactions linked to their clinical uses.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Conducta/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas , Cognición/efectos de los fármacos , Diabetes Mellitus/inducido químicamente , Interacciones Farmacológicas , Dislipidemias/tratamiento farmacológico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedades Renales/inducido químicamente , Estructura Molecular , Enfermedades Musculares/inducido químicamente
20.
Artículo en Inglés | MEDLINE | ID: mdl-26830535

RESUMEN

To investigate the effect of Shexiang Baoxin Pill (SBP), a tranditional Chinese medicine, on the pharmacokinetic (PK) parameters of simvastatin in healthy volunteers' plasma, a quantitative method was developed using an Agilent G6410A rapid performance liquid chromatography (RPLC) coupled with triple quadrupole mass spectrometry system. The established method was rapid with high extraction recovery and successfully applied for the determination of simvastatin in plasma of 16 healthy volunteers. The results demonstrated that the MRT(0-∞), T1/2 and Tmax value of simvastatin were significantly decreased, while the AUC(0-t) and Cmax values of smivastatin were increased by SBP. The pharmacokinetic study demonstrated that the metabolism parameters of simvastatin could be affected by SBP and the potential drug-drug interaction should be noted in the future clinical practice.


Asunto(s)
Medicamentos Herbarios Chinos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Simvastatina/farmacocinética , Adulto , Medicamentos Herbarios Chinos/administración & dosificación , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Estándares de Referencia , Simvastatina/administración & dosificación
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