Pharmacokinetics of boldine in control and Mrp2-deficient rats.

The aim of the present study was to describe the currently poorly understood pharmacokinetics (PK) of boldine in control rats (LW, Lewis rats), and Mrp2 transporter-deficient rats (TR(-)). Animals from the LW and TR(-) groups underwent a bolus dose study with 10 mg/kg of boldine applied either orally or intravenously in order to evaluate the major PK parameters. The TR(-) rats demonstrated significantly reduced total clearance with prolonged biological half-life (LW 12+/-4.6 versus TR(-) 20+/-4.4 min), decreased volume of distribution (LW 3.2+/-0.4 l/kg versus TR(-) 2.4+/-0.4 l/kg) and reduced bioavailability (LW 7 % versus TR(-) 4.5 %). Another set of LW and TR(-) rats were used for a clearance study with continuous intravenous administration of boldine. The LW rats showed that biliary and renal clearance formed less than 2 % of the total clearance of boldine. The treatment of samples with beta-glucuronidase showed at least a 38 % contribution of conjugation reactions to the overall clearance of boldine. The TR(-) rats demonstrated reduced biliary clearance of boldine and its conjugates, which was partly compensated by their increased renal clearance. In conclusion, this study presents the PK parameters of boldine and shows the importance of the Mrp2 transporter and conjugation reactions in the elimination of the compound.

Boldine attenuates cholestasis associated with nonalcoholic fatty liver disease in hereditary hypertriglyceridemic rats fed by high-sucrose diet.

The aim of the current study was to clarify the effect of high sucrose diet (HSD) on bile formation (BF) in rats with hereditary hypertriglyceridemia (HHTg). Potentially positive effects were studied for boldine, a natural choleretic agent. Administration of HSD to HHTg rats led to increased triglyceride deposition in the liver. HSD reduced BF as a consequence of decreased biliary secretion of bile acids (BA) and glutathione. Responsible mechanism was down-regulation of hepatic transporters for BA and glutathione, Bsep and Mrp2, respectively. Moreover, gene expressions of transporters for other constituents of bile, namely Abcg5/8 for cholesterol, Abcb4 for phospholipids, and Oatp1a4 for xenobiotics, were also reduced by HSD. Boldine partially attenuated cholestatic effect of HSD by promotion of biliary secretion of BA through up-regulation of Bsep and Ntcp, and by increase in biliary secretion of glutathione as a consequence of its increased hepatic disposition. This study demonstrates mechanisms of impaired BF during nonalcoholic fatty liver disease induced by HSD. Altered function of responsible transporters suggests also potential for changes in kinetics of drugs, which may complicate pharmacotherapy in subjects with high intake of sucrose, and with fatty liver disease. Sucrose induced alterations in BF may be alleviated by administration of boldine.