The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics

Abstract

Berberine (BBR) has extremely low concentration and high tissue distribution. However, current pharmacokinetic studies predominantly focus on its concentration in plasma, which could hardly make a comprehensive understanding of its pharmacokinetic process. This study made a pioneering endeavor to explore the erythrocyte-hemoglobin (Hb) self-assembly system of BBR by exploring the interaction of BBR with erythrocyte and the combination of BBR with Hb. Results showed that BBR had a low bioavailability ( C 0 = 2.833 μg/mL via intravenous administration of 2.5 mg/kg BBR and C max = 0.260 μg/mL via oral administration of 400 mg/kg BBR). Besides, BBR achieved higher concentrations in erythrocytes than plasma, and the erythrocytes count and Hb content were significantly decreased after intravenous administration. Hemolysis rate indicated the BBR-erythrocyte system (with 2% erythrocytes) was relatively stable without hemolysis at the concentration of 1.00 mg/mL. And the maximum percentage of drug loading was 100% when the BBR-erythrocyte concentration was 0.185 μg/mL. Furthermore, incubation of BBR and erythrocytes resulted in internalization of the erythrocyte membrane and the formation of intracellular vacuoles. The thermodynamic parameters indicated that the binding process of bovine hemoglobin (BHB) and BBR was spontaneous. UV-vis absorption spectra, synchronous fluorescence, circular dichroism and Raman spectra collectively indicated that BBR showed strong binding affinity toward BHB and affected the molecular environment of residues like tryptophan and tyrosine in BHB, resulting in the conformational changes of its secondary and tertiary structure. Molecular docking indicated BBR interacted with Arg-141 residue of BHB via hydrogen bond with the bond length of 2.55 Å. The ΔG value of the BHB-BBR system was −31.79 kJ/mol. Molecular dynamics simulation indicated the root mean square derivation of BBR-BHB was <0.025 nm, suggestive of stable conformation. Cumulatively, there was an erythrocyte-Hb self-assembled drug delivery system after oral or intravenous administration of BBR, which conceivably gained novel insight into the discrepancy between the extremely low plasma concentration and relatively high tissue concentration of BBR.

Anti-Inflammatory Activation of Phellodendri Chinensis Cortex is Mediated by Berberine Erythrocytes Self-Assembly Targeted Delivery System

“… 26 In our previous work, a BBR erythrocytes-Hb self-assembly delivery system has been identified and the accumulation of BBR in erythrocytes was attributed to the intense conjugation of BBR with Hb. 12 In this study, BBR achieved a significantly higher concentration in erythrocytes than in plasma in rats after intragastrical administration with PCC and intraperitoneal administration with BBR, which was in agreement with our previous findings. 12 , 13 HCl, a hydrolyzing agent, could be used for the hydrolysis of drug-Hb adducts.…”

“… 24 Erythrocytes harbor various distinctive properties such as unmatched long circulation, biocompatibility and biodegradability that make them appealing vascular carriers for in vivo delivery of natural and synthetic payloads. 9 , 25 Although our previous study has suggested a BBR erythrocytes-Hb self-assembly delivery system, 12 the metabolic aspect, targeted delivery and dose–effect relationship of BBR mediated by erythrocytes have not yet been clearly clarified.…”

“… 10 , 11 In our recent work, we have found that BBR could bind to Hb assembly and form a BBR-erythrocytes drug delivery system. 12 Furthermore, oxyberberine (OBB, Figure 1 ), whose C-9 position is oxidized to a carbonyl group to form an amide ring with 8-N atoms, has been identified as the essential metabolite after intravenous administration of BBR in our previous study. 13 Erythrocytes are equipped with various reactive oxygen species and enzymes to catalyze drug metabolism, particularly drug oxidation.…”

Network Pharmacology and Molecular Docking Analyses Unveil the Mechanisms of Yiguanjian Decoction against Parkinson’s Disease from Inner/Outer Brain Perspective

“…After Genetic Algorithm was used for the calculating, the Autodock program was run for the second docking operation [ 29 ]. The binding energy was calculated and successful docking was defined by a binding energy of ≤ -5 kJ/mol [ 30 ]. Figures of the selected binding sites were generated using PyMOL software…”

Pharmacokinetic of berberine, the main constituent of Berberis vulgaris L.: A comprehensive review

“…In an animal study in rats, berberine (2.5 mg/kg) was administered intravenously and C 0 was 2.833 μg/ml and when a dose of 400 mg/kg berberine was administered orally in rats, Cmax was 0.260 μg/ml. AUC 0−t was also found to be low in both mentioned routes of administration (Yu et al, 2022).…”