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, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine.
- MeSH
- ABC transportéry nedostatek genetika metabolismus MeSH
- aplikace orální MeSH
- aporfiny aplikace a dávkování metabolismus farmakologie MeSH
- buňky Hep G2 MeSH
- buňky MDCK MeSH
- cholagoga a choleretika aplikace a dávkování metabolismus farmakologie MeSH
- ethinylestradiol farmakologie MeSH
- genetická transkripce účinky léků MeSH
- glutathion metabolismus MeSH
- hepatobiliární exkrece MeSH
- intravenózní infuze MeSH
- játra účinky léků metabolismus MeSH
- kinetika MeSH
- lidé MeSH
- osmóza MeSH
- potkani inbrední LEW MeSH
- potkani transgenní MeSH
- potkani Wistar MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- psi MeSH
- receptory cytoplazmatické a nukleární agonisté genetika metabolismus MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- upregulace MeSH
- žluč metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
