Abstract
The natural alkaloid berberine has been ascribed numerous health benefits including lipid and cholesterol reduction and improved insulin sensitivity in diabetics. However, oral (PO) administration of berberine is hindered by poor bioavailability and increasing dose often elicits gastro-intestinal side effects. To overcome the caveats associated with oral berberine, we developed transdermal (TD) formulations of berberine (BBR) and the berberine precursor dihydroberberine (DHB). These formulations were compared to oral BBR using pharmacokinetics, metabolism, and general safety studies in vivo. To complete this work, a sensitive quantitative LC-MS/MS method was developed and validated according the FDA guidelines for bioanalytical methods to simultaneously measure berberine, simvastatin, and simvastatin hydroxy acid with relative quantification used for the berberine metabolite demethylene berberine glucuronide (DBG). Acute pharmacokinetics in Sprague-Dawley rats demonstrated a statistically relevant ranking for berberine bioavailability based upon AUC0-8 as DHB TD > BBR TD >> BBR PO with similar ranking for the metabolite DBG, indicating that transdermal administration achieves BBR levels well above oral administration. Similarly, chronic administration (14 days) resulted in significantly higher levels of circulating BBR and DBG in DHB TD treated animals. Chronically treated rats were given a single dose of simvastatin with no observed change in the drugs bioavailability compared with control, suggesting the increased presence of BBR had no effect on simvastatin metabolism. This observation was further supported by consistent CYP3A4 expression across all treatment groups. Moreover, no changes in kidney and liver biomarkers, including alanine aminotransferase and alkaline phosphatase, were observed between treatment formats, and confirming previous reports that BBR has no effect on HMG-CoA expression. This study supports the safe use of transdermal compositions that improve on the poor bioavailability of oral berberine and have the potential to be more efficacious in the treatment of dyslipidemia or hypercholesterolemia.
Highlights
Berberine (BBR) is a natural alkaloid found in a variety of plant species including barberry (Berberis), meadow rue (Thalictrum), celandine (Chelidonium), and goldenseal (Hydrastis canadensis) [1,2,3,4]
Molecular ions were most abundant for berberine [M]+ and simvastatin [M+H]+ and their corresponding internal standards
Multi-analyte quantification in low volumes of rat serum was facilitated by the development of a concurrent and sensitive LC-MS/MS method
Summary
Berberine (BBR) is a natural alkaloid found in a variety of plant species including barberry (Berberis), meadow rue (Thalictrum), celandine (Chelidonium), and goldenseal (Hydrastis canadensis) [1,2,3,4]. BBR has been investigated for a variety of health benefits including antimicrobial [5,6], anti-inflammatory [7], chemotherapeutic [8], anti-diabetic [9,10], as well as cholesterol and lipid-lowering properties [11,12]. Regarding the latter, berberine is widely used in humans as a natural supplement to aid the management of dyslipidemia [13]. Oral formulations may unavoidably encounter gastrointestinal side effects and the use of complex non-medicinal excipients or processes may complicate the clinical translation and commercialization of such products
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
