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 TisularRESUMEN
Red yeast rice (RYR) can reduce cholesterol through its active component, lovastatin. This study was to investigate the pharmacokinetic properties of lovastatin in RYR products and potential RYR-drug interactions. Extracts of three registered RYR products (LipoCol Forte, Cholestin, and Xuezhikang) were more effective than pure lovastatin in inhibiting the activities of cytochrome P450 enzymes and P-glycoprotein. Among CYP450 enzymes, RYR showed the highest inhibition on CYP1A2 and CYP2C19, with comparable inhibitory potencies to the corresponding typical inhibitors. In healthy volunteers taking the RYR product LipoCol Forte, the pharmacokinetic properties of lovastatin and lovastatin acid were linear in the dose range of 1 to 4 capsules taken as a single dose and no significant accumulation was observed after multiple dosing. Concomitant use of one LipoCol Forte capsule with nifedipine did not change the pharmacokinetics of nifedipine. Yet, concomitant use of gemfibrozil with LipoCol Forte resulted in a significant increase in the plasma concentration of lovastatin acid. These findings suggest that the use of RYR products may not have effects on the pharmacokinetics of concomitant comedications despite their effects to inhibit the activities of CYP450 enzymes and P-gp, whereas gemfibrozil affects the pharmacokinetics of lovastatin acid when used concomitantly with RYR products.
RESUMEN
The intestinal facilitated glucose transporter, GLUT2, is a high-turnover transport system and is important to handle the large transepithelial substance flux. Since intestinal GLUT2 is normally located at the basolateral side, glucose uptake in the presence of flavonoids was measured using basolateral membrane vesicles (BLMV) isolated from the rat jejunum to investigate the interaction between flavonoids and intestinal facilitated glucose transporters. In addition, basolateral uptake of flavonoids was studied in Caco-2 cells. As a result, in the BLMV study most flavonoids (glycosides or aglycones) at 0.1 mM inhibited glucose uptake in BLMV; epicatechin gallate (ECG) showed the highest inhibitory activity (about 33%), followed by quercetin 3-O-glucoside (Q3G), fisetin and gossypin (about 25-28% inhibition). The dose-response study showed that the IC50 values for ECG and Q3G on glucose uptake in BLMV were 294+/-89 microM and 357+/-52 microM, respectively. Kinetic analyses showed that ECG and Q3G competitively inhibited glucose uptake in BLMV with inhibition constants (Ki) of 332+/-42 microM and 404+/-45 microM, respectively. In Caco-2 cells, basolateral uptake of Q3G was significantly inhibited by phloretin, a GLUT2 inhibitor (0.40+/-0.05 vs. 0.24+/-0.03 nmole/mg protein without aand with phloretin, respectively). On the other hand, phloretin did not show inhibitory activity on basolateral uptake of ECG in Caco-2 cells (1.26+/-0.05 vs. 1.22+/-0.07 nmole/mg protein without and with phloretin, respectively). The data showed that the intestinal facilitated glucose transporter recognizes a variety of flavonoids with or without conjugation. In addition, GLUT2 can be responsible for the transport of Q3G across the intestinal basolateral membrane.