The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.
Background and Purpose: Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug-drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug-drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice. Methods: A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9-21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated. Results: Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC 0-48h and C max of nifedipine by 83% (90% confidence interval [CI] 1.46-2.31) and 64% (90% CI 1.34-2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC 0-t and C max of S-warfarin by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39), respectively. Conclusion: Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug-drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.
PurposeThe aim of this study was to evaluate the bioequivalence of a generic product 70 mg alendronate sodium tablets with the reference product Fosamax® 70 mg tablet.Materials and methodsA single-center, open-label, randomized, three-period, three-sequence, reference-replicated crossover study was performed in 36 healthy Chinese male volunteers under fasting conditions. In each study period, the volunteers received a single oral dose of the generic or reference product (70 mg). Blood samples were collected at pre-dose and up to 8 h after administration. The bioequivalence of the generic product to the reference product was assessed using the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reference-scaled average bioequivalence (RSABE) methods.ResultsThe average maximum concentrations (Cmax) of alendronic acid were 64.78±43.76, 56.62±31.95, and 60.15±37.12 ng/mL after the single dose of the generic product and the first and second doses of the reference product, respectively. The areas under the plasma concentration–time curves from time 0 to the last timepoint (AUC0–t) were 150.36±82.90, 148.15±85.97, and 167.11±110.87 h⋅ng/mL, respectively. Reference scaling was used because the within-subject standard deviations of the reference product (sWR) for Cmax and AUC0–t were all higher than the cutoff value of 0.294. The 95% upper confidence bounds were −0.16 and −0.17 for Cmax and AUC0–t, respectively, and the point estimates for the generic/reference product ratio were 1.08 and 1.00, which satisfied the RSABE acceptance criteria of the FDA. The 90% CIs for Cmax and AUC0–t were 90.35%–129.04% and 85.31%–117.15%, respectively, which were within the limits of the EMA for the bioequivalence of 69.84%–143.19% and 80.00%–125.00%.ConclusionThe generic product was bioequivalent to the reference product in terms of the rate and extent of alendronate absorption after a single 70 mg oral dose under fasting conditions.
Patrinia villosa (Thunb.) Juss is a Chinese edible herbal widely used in China for treatment of carbuncles, acute appendicitis, hepatitis and stasis for hundreds of years. In this study, the antitumor effects and the possible mechanisms of total saponin extract from P. villosa (SPV) and total flavonoid extract from P. villosa (FPV) were investigated in four cancer cell lines including mouse melanoma cell line B16, MCF-7 human breast cancer cells, Hela human epithelial cervical cancer cells and L1210 mouse lymphocytic leukemia cells. The antiproliferative effects of SPV and FPV on these cells were observed by 3-(4,5-Dimethyithiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The cell cycle was detected by flow cytometry. The expression of CDK4 and cyclin D1 were measured by western blot. The results of MTT assay suggested that FPV showed much stronger antiproliferative effects on L1210 cells in a dose-dependent manner. On the other hand, SPV showed better antiproliferative effect than FPV on the other three cell lines in a dose-dependent manner. The mechanism of antitumor effect of SPV and FPV might be the inhibition of expression of CDK4 and cyclin D1, and accordingly arrested four cancer cell lines in G0/G1 phase, decreased the number of cells in S phase, and finally induced antiproliferative effect. In summary, pharmacological data obtained from this study suggested that SPV and FPV possessed cancer chemopreventive potential on different types of cancer cells. These results were much more favorable on bioactivity-guided isolations of SPV and FPV.
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