Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties

ABSTRACT

Introduction

Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability.

Areas covered

Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed.

Expert opinion

Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR.

KEYWORDS:

• Berberine
• bioavailability
• first-pass metabolism
• active metabolites
• lipophilic metabolites

Article highlights

• In rats, the absolute oral bioavailability of berberine (BBR) is quite low, <1% of the dose, mostly due to the high intestinal first-pass metabolism (more than 98% of the absorbed amount), insufficient intestinal absorption (about 50% of dose), and hepatic first-pass metabolism (20–30% of that reached portal vein).

• The insufficient intestinal absorption of BBR comes from the low solubility and P-glycoprotein (P-gp)-mediated efflux transport. BBR forms lipophilic salts/ion-pair complexes with various anionic salts, and the solubility of the complex is variable depending on the counter ions. In addition, BBR can cause P-gp-mediated drug–drug interactions.

• The intestinal CYPs-mediated first-pass metabolism is the main reducing factor of oral bioavailability of BBR. Many active metabolites are generated after intestinal first-pass metabolism. Biliary excreted phase-II metabolites of berberine are hydrolyzed by microbiota β-glucuronidase/sulfatase and undergo enterohepatic circulation.

• Intestinal microbiota-mediated metabolism generates lipophilic metabolites, including berberrubine (BRB), an active metabolite with higher distribution volume, and dihydroberberine (DHBBR), a precursor that can deliver BBR into the brain by the redox system. BRB is metabolized into glucuronide conjugate in the intestine/liver, subjected to enterohepatic circulation and exerts pharmacological activity.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.