Pharmacokinetic interaction between peimine and paeoniflorin in rats and its potential mechanism.

CONTEXT: Peimine and paeoniflorin can be combined for the treatment of cough in paediatrics. The interaction during the co-administration could dramatically affect the bioavailability of drugs. OBJECTIVE: The interaction between peimine and paeoniflorin was investigated in this study. MATERIALS AND METHODS: The pharmacokinetics of paeoniflorin (20 mg/kg) with or without the coadministration of peimine (5 mg/kg for 10 days before paeoniflorin) was orally investigated in Sprague-Dawley rats (n = 6). The group without the peimine was set as the control group. The metabolic stability of paeoniflorin was studied in rat liver with microsomes. The effect of peimine on the absorption of paeoniflorin was investigated with Caco-2 cell monolayers. RESULTS: The Cmax (244.98 ± 10.95 vs. 139.18 ± 15.14 µg/L) and AUC(0-t) (3295.92 ± 263.02 vs. 139.18 ± 15.14 h·µg/L) of paeoniflorin was increased by peimine. The t1/2 was prolonged from 5.33 ± 1.65 to 14.21 ± 4.97 h and the clearance was decreased from 15.43 ± 1.75 to 4.12 ± 0.57 L/h/kg. Consistently, peimine increased the metabolic stability of paeoniflorin with rat liver microsomes with the increased t1/2 (56.78 ± 2.62 vs. 26.33 ± 3.15 min) and the decreased intrinsic clearance (24.42 ± 3.78 vs. 52.64 ± 4.47 µL/min/mg protein). Moreover, the transportation of paeoniflorin was also inhibited by peimine as the efflux ratio decreased from 3.06 to 1.63. DISCUSSION AND CONCLUSIONS: Peimine increased the systemic exposure of paeoniflorin through inhibiting the activity of CYP3A4 and P-gp. These results provide a reference for further in vivo studies in a broader population.

ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of prostate cancer by sponging miR-4739 to upregulate MEF2D.

Prostate cancer (PCa) is a destructive malignancy with a bad prognosis. LncRNA VPS9D1-AS1 has recently been delineated as an oncogene in some kinds of tumor, whereas, the function of VPS9D1-AS1 in PCa remains to be clarified. In this study, we researched its underlying role in PCa. The expression of VPS9D1-AS1 was conspicuously upregulated in PCa tissues and cells. And absence of VPS9D1-AS1 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in PCa. In addition, VPS9D1-AS1 overexpression led to opposite results. Furthermore, VPS9D1-AS1/MEF2D could sponge with miR-4739. VPS9D1-AS1/MEF2D and miR-4739 were inversely correlated in tumor cells. And the expression of miR-4739 is markedly downregulated in PCa, meanwhile, that of MEF2D exhibited the opposite tendency. However, MEF2D was positively regulated by VPS9D1-AS1. Moreover, MEF2D upregulation offset the suppressive effects of VPS9D1-AS1 deficiency on cell proliferation, migration and invasion in PCa. Additionally, ZEB1 contained the binding sites of VPS9D1-AS1 promoter, and there existed positive relation between them. Taken together, above results illustrated that ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of PCa by sponging miR-4739 to upregulate MEF2D, which offering a new useful reference for studying the development process of PCa.