ABSTRACT
The main purpose of the present study was to fabricate mucoadhesive bio-nanocomposite hydrogels to prolong the drug retention time in the stomach. In these bio-nanocomposite hydrogels, chitosan (CH) was used as a bioadhesive matrix, montmorillonite (MMT) was applied to modulate the release rate, and tripolyphosphate (TPP) was the cross-linking agent. The test samples were analyzed via different methods such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). Drug incorporation efficacy and mucoadhesive strength of these nanocomposite hydrogel beads were studied. Swelling and in vitro drug release behaviors of these bio-nanocomposite hydrogels were evaluated in simulated gastric fluid (SGF; pH 1.2). The optimized MMT-famotidine (FMT)/CH bio-nanocomposite hydrogels displayed a controllable and sustainable drug release profile with suitable mucoadhesion and prolonged retention time in the stomach. Thus, the results demonstrated that the fabricated mucoadhesive bio-nanocomposite hydrogels could remarkably increase the therapeutic efficacy and bioavailability of FMT by the oral route.
ABSTRACT
BACKGROUND: Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N-desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. METHODS: The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 µg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. RESULTS: Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC(0-120) of the parent drug demonstrated 50% increase and AUC(0-120) of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CLh) and intrinsic clearance (Clint) showed 20% and 60% decrease in treatment group compared to control group. CONCLUSION: All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In conclusion, this study is the first investigation of MRZ metabolism in presence of MDMA in isolated perfused rat liver model.
