Evaluation of the pharmacokinetics, chylomicron inhibition, and toxicity of colchicine in rats given low doses.

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.

Oxidative stress in testes of rats exposed to n-butylparaben.

This study was aimed at determining if oxidative stress imbalance in testes of rats occurs after n-butylparaben (n-ButP) exposure. Young male Sprague-Dawley rats were subcutaneously treated with n-ButP during one spermatogenic cycle (57 days) at 0 (control-oil), 150, 300 and 600 mg/kg/d with peanut oil as vehicle. A non-vehicle control group was also included. Antioxidant enzyme activities (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) and levels of reduced and oxidized glutathione were measured in testes. Lipid peroxidation and H2O2 concentrations were also assessed. Results showed an increase of oxidative stress in oil-treated groups, excepting 600 mg/kg/d, suggesting oxidative stress due to peanut oil. A possible antioxidant effect due to n-ButP and its metabolites was suggested at 600 mg/kg/d, the only group not showing oxidative stress. An increase of calcium concentration in testes was also observed. On the other hand, a physiologically-based pharmacokinetic (PBPK) model was developed and the concentrations of n-ButP and its metabolites were simulated in plasma and testes. The peak concentration (Cmax) in testes was found slightly higher than that in plasma. The current results indicate that peanut oil can cause oxidative stress while high doses of n-ButP can act as antioxidant agent in testes.

Nanoemulsion-based electrolyte triggered in situ gel for ocular delivery of acetazolamide.

In the present work the antiglaucoma drug, acetazolamide, was formulated as an ion induced nanoemulsion-based in situ gel for ocular delivery aiming a sustained drug release and an improved therapeutic efficacy. Different acetazolamide loaded nanoemulsion formulations were prepared using peanut oil, tween 80 and/or cremophor EL as surfactant in addition to transcutol P or propylene glycol as cosurfactant. Based on physicochemical characterization, the nanoemulsion formulation containing mixed surfactants and transcutol P was selected to be incorporated into ion induced in situ gelling systems composed of gellan gum alone and in combination with xanthan gum, HPMC or carbopol. The nanoemulsion based in situ gels showed a significantly sustained drug release in comparison to the nanoemulsion. Gellan/xanthan and gellan/HPMC possessed good stability at all studied temperatures, but gellan/carbopol showed partial drug precipitation upon storage and was therefore excluded from the study. Gellan/xanthan and gellan/HPMC showed higher therapeutic efficacy and more prolonged intraocular pressure lowering effect relative to that of commercial eye drops and oral tablet. Gellan/xanthan showed superiority over gellan/HPMC in all studied parameters and is thus considered as a promising mucoadhesive nanoemulsion-based ion induced in situ gelling formula for topical administration of acetazolamide.