Impact of solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats

Abstract

In the current investigation, the alkaloid colchicine was administered intravenously to male Wistar rats both as a solution in isotonic sodium chloride (NaCl 0.9%, control group) and in NaCl 0.9%:Solutol HS 15 (95:5) at 1.5 mg/kg. At predetermined time points, plasma and urine were collected from the animals and analysed for colchicine and its demethylated metabolites by LC/MS-MS. In the presence of Solutol HS 15, colchicine clearance (CI) was significantly decreased and its maximum plasma concentration (c(max)) was significantly increased as compared to the control group (CI: 15.6+/-7.0 ml/min/kg vs 34.3+/-2.3 ml/min/kg; c(max) 3055.1+/-587.4 h vs 1260.1+/-223.7 h; p<0.05). Moreover, the amount of parent colchicine excreted into urine was markedly increased in the Solutol HS 15 treated group (41.50+/-3.23 vs 1.17+/-0.41% of total dose; p<0.05). By contrast, there was no statistically significant difference but a trend to lower values only in the volume of distribution (V(d) 13.3+/-2.2 l/h vs 31.4+/-17.7 l/h, p=0.35). The half-lives for the first (t(1/2 1stphase). 0.21+/-0.02 h vs 0.20+/-0.03 h) and second phase (t(1/2 2ndphase). 18.5+/-6.9 h vs 18.3+/-7.7 h) did not differ significantly in dependence on the dosing vehicle. The free fraction in rat plasma (FF), the blood/plasma (lambda) and erythrocyte/plasma concentration ratios (K(e)) were not significantly changed in the presence of different concentrations of Solutol HS 15 compared with surfactant-free incubations (overall means: 72.25+/-0.50% for FF, 0.80+/-0.02 for lambda, 0.46+/-0.04 for K(e)). In vitro, in rat hepatocytes, the clearance of colchicine was significantly reduced at 0.003% Solutol HS 15 present in the incubation medium (0.86+/-0.15 microl/min/10(-6) cells vs 1.46+/-0.06 microl/min/10(-6) cells). As colchicine exhibits a comparatively high aqueous solubility, an impact of Solutol HS 15 on the solubility of the alkaloid is very unlikely to be a reason for the observed effect. Therefore, our results indicate that the most likely reasons for the changed pharmacokinetic behaviour of colchicine in the presence of Solutol HS 15 are alterations of metabolism and/or transport as well as distribution and elimination processes.

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour

“…Clear marble burying is shown following vehicle treatment (d), whereas CBD significantly reduced it at 2 h, but not 6 h post-injection literature (∼7-10%) may be devoid of such side effects. Drug pharmacokinetics are subject to vehicle-induced changes in absorption and exposure (Cornaire et al 2004), and our data are in line with the notion that solutol can increase plasma C max and overall exposure of drugs compared to other solvents (Bittner et al 2003). Whether the enhanced concentration of CBD in plasma and brain administered in solutol was due to heightened solubility in gastrointestinal fluids or increased drug permeability remains uncertain.…”

Physiological Modeling to Understand the Impact of Enzymes and Transporters on Drug and Metabolite Data and Bioavailability Estimates

“…N-Trimethyl chitosan chloride acts as a potential absorption enhancer by opening tight junctions of intestinal epithelial cells to allow increased transport of hydrophilic compounds through the paracellular transport pathway (23,24). In other instances, excipients are found to reduce hepatocyte uptake (25,26) and/or the activity of enzymes and decrease the metabolic intrinsic clearance (27,28). Therefore, important components of pharmaceutical formulations that affect improvement of formulation characteristics can reduce the effectiveness of some preparations and result in variations in BA and BE with use of different excipients.…”

Kolliphor® HS 15 Micelles for the Delivery of Coenzyme Q10: Preparation, Characterization, and Stability

“…Eur) monographs, and it has an import registration certificate in China. HS15 has been found to enable poorly soluble drugs to enhance the solubilization (18)(19)(20) and to inhibit to some degree the P-glycoprotein efflux mechanism (21,22). Thus, HS15 greatly increases the transportation of drug in the systemic circulation for poorly soluble drugs, further boosting the bioavailability.…”