Poor permeability and absorption affect the activity of four alkaloids from Coptis

Abstract

Coptidis rhizoma (Coptis) and its alkaloids exert various pharmacological functions in cells and tissues; however, the oral absorption of these alkaloids requires further elucidation. The present study aimed to examine the mechanism underlying the poor absorption of alkaloids, including berberine (BER), coptisine (COP), palmatine (PAL) and jatrorrhizine (JAT). An ultra‑performance liquid chromatography (UPLC) method was validated for the determination of BER, COP, PAL and JAT in the above experimental medium. In addition, the apparent oil‑water partition coefficient (Po/w); apparent permeability coefficient (Papp), determined using a parallel artificial membrane permeability assay (PAMPA) plate; membrane retention coefficient (R %); and effect of P‑glycoprotein (P‑gp) inhibitor on the Papp of the four alkaloids were investigated. The intestinal absorption rate constant (Ka) and absorption percentage (A %) of the four alkaloids were also determined. The results of the present study demonstrated that the Po/w of the four alkaloids in 0.1 mol·l‑1 HCl medium was significantly higher (P<0.01), compared with those of the alkaloids in phosphate buffer (pH 7.4). The Papp of BER was 1.0‑1.2x10‑6 cm·s‑1, determined using a PAMPA plate, and the Papp of BER, COP, PAL and JAT decreased sequentially. The concentrations of the four alkaloids on the apical‑to‑basolateral (AP‑BL) surface and the basolateral‑to‑apical (BL‑AP) surface increased in a linear manner, with increasing concentrations between 10 and 100 µmol. In addition, the transportation of BER on the BL‑AP surface was significantly faster (P<0.01), compared with that on the AP‑BL surface and, following the addition of verpamil (a P‑gp inhibitor), the Papp (AP‑BL) of the four alkaloids increased, whereas the Papp (BL‑AP) was significantly decreased (P<0.01). The rat intestinal perfusion experiment demonstrated that the four alkaloids were poorly absorbed; however, the Ka of BER was significantly higher, compared with the three other alkaloids. Furthermore, the A % and Ka provided evidence that the absorption of BER was increased in the jejunum, compared with in the ileum. In conclusion, the four alkaloids from Coptis appeared to be poorly absorbed, determined using a shake flask, pre‑coated PAMPA plates, a Caco‑2 cell monolayer model and intestinal perfusion; however, absorption was higher in the jejunum than in the ileum. Among the four alkaloids, the permeability of BER was markedly higher than the others, and P‑gp efflux had a significant effect on the absorption of those alkaloids.

Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

“…In addition, previous pharmacokinetic investigations proved that after oral administration of Rhizoma coptidis extract, the plasma concentrations of its prototype alkaloids were so low that their systemic therapeutic actions cannot be explained . The contradiction between the definite biological activities and the poor permeability and absorption of alkaloids promoted the hypothesis that the metabolites of the alkaloids may also exert biological activities. Thus, finding a suitable pharmacokinetic marker for Rhizoma coptidis alkaloids may be challenging but is necessary …”

Different structures of berberine and five other protoberberine alkaloids that affect P-glycoprotein-mediated efflux capacity

“…The synthesized BBR analog pseudoberberine (IMB-Y53) has a low affinity to P-gp and exhibits improved bioavailability and a higher glucose-lowering efficacy compared to BBR [50,51]. Moreover, some PAs, such as coptisine, have trivial structural differences from BBR but have been demonstrated to have very different binding affinities to Pgp [52]. It is crucial to clarify why such small structural differences can lead to substantial efflux capacity differences, which is essential for the design and optimization of the current PAs.…”

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…As with other diseases, the therapeutic potential of berberine for cancer is also mediated through effect on diverse cellular targets and signalling processes (see Section 2 below). Despite its promise, however, berberine is known for its relatively poor anticancer efficacy and poor bioavailability resulting from low intestinal permeability and absorption [20] and efflux due to the action of intestinal permeabilityglycoprotein (P-gp) [21]. Furthermore, berberine is extensively metabolised in the liver by the action of enzymes which are also active in intestinal cells [22].…”

“…Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.Molecules 2020, 25, 1426 2 of 31 cellular targets and signalling processes (see Section 2 below). Despite its promise, however, berberine is known for its relatively poor anticancer efficacy and poor bioavailability resulting from low intestinal permeability and absorption [20] and efflux due to the action of intestinal permeability-glycoprotein (P-gp) [21]. Furthermore, berberine is extensively metabolised in the liver by the action of enzymes which are also active in intestinal cells [22].…”