RESUMEN
Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.
Asunto(s)
Crizotinib , Citocromo P-450 CYP3A , Microsomas Hepáticos , Ratas Sprague-Dawley , Tramadol , Animales , Tramadol/farmacología , Crizotinib/farmacología , Ratas , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Masculino , Interacciones Farmacológicas , Humanos , Espectrometría de Masas en Tándem , Familia 2 del Citocromo P450/metabolismo , Familia 2 del Citocromo P450/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Analgésicos Opioides/farmacologíaRESUMEN
OBJECTIVE: To study the curative effects of pirfenidone (PF) on pulmonary fibrosis induced by paraquat (PQ) in mice and to provide the theoretical basis for clinical treatment. METHODS: Ninety adult healthy male ICR mice were randomly divided into six groups: control group, PQ group, 2 mg/kg Dexamethasone group, 25 mg/kg PF group, 50 mg/kg PF group and 100 mg/kg PF group, there were 15 mice in each group. The corresponding volume of normal saline was given to the each mouse in control group according to the weight, after 2 h 0.1% CMC was given to the each mouse of control group one time by intragastric administration, then the CMC was administrated at regular time until sacrifice. All mice for other 5 groups were exposed to 100 mg/kg PQ by intragastric administration. At 2 h after exposure to PQ, 0.02 ml/10 g dexamethasone and 25, 50, 100 mg/kg PF were given to mice for dexamethasone group and for 3 PF groups by intragastric administration each day for 49 days, respectively. The lung coefficient was calculated and pathological changes of lung tissue were observed by HE staining for each mouse. The hydroxyproline (HYP) level in lung tissue was measured for each mouse. The mRNA level of and the protein level of TGF-ß(1) in lung tissue for each mouse were determined, and the protein level of TGF-ß(1) in the bronchus-alveolus lavage fluid (BALF) of each mouse was detected. RESULTS: The survival rates on the 3rd day in PQ group, 3 PF groups and dexamethasone group were 53.33%, 46.67%, 73.33%, 86.67% and 80%, respectively. The survival rates on the 3rd day in dexamethasone group, 50 mg/kg and 100 mg/kg PF groups were significantly higher than those of PQ group and 25 mg/kg PF group (P < 0.05). The lung coefficients of 3 PF groups were significantly lower than that of the PQ group (P < 0.05). The lung tissue HYP levels of dexamethasone group and 3 PF groups were 50.95 ± 11.65, 44.52 ± 9.48, 43.27 ± 6.01 and 40.82 ± 5.90 mg/g respectively, which were significantly lower than that (74.27 ± 3.68) of PQ group (P < 0.01). The TGF-ß(1) protein levels of BALF in dexamethasone group, 50 and 100 mg/kg PF groups were 22.03 ± 7.27, 27.75 ± 5.84 and 21.31 ± 6.82 ng/ml respectively, which were significantly lower than that (52.52 ± 15.51) ng/ml of PQ group (P < 0.01) The expression level of TGF-ß(1) mRNA in 100 mg/kg PF group decreased significantly, as compared with PQ group (P < 0.01). CONCLUSION: PF could reduce the collagen deposition and pulmonary fibrosis induced by PQ in mice lungs.