Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study

Abstract

Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.

Oral Pharmacokinetics of Hydroxycinnamic Acids: An Updated Review

“…The transport was linear and independent of concentration, a characteristic of the transcellular passive diffusion mechanism [109], contrasting with the outcomes reported by Konishi and Shimizu [96]. Additionally, in the T84 cell line, among CA, CGA, p-COA and FA, only FA was detected on the basolateral side, demonstrating that it is the most permeable HCA and confirming the results shown by the PAMPA and Caco-2 cell methods [81,82,96,110].…”

“…In another study, an even lower Papp value, expressed as the logarithm of (log Papp = −5.52 or Papp~3 × 10 −6 cm/s), was found for CA, CGA and RA in the pH r 4.0-8.0. These Papp values mean that less than 1% of each HCA was transported tow the receptor compartment [81][82][83]. A higher transport rate was only observed for F pH 4.0, for which the log Papp was −4.77 (Papp~17 × 10 −6 cm/s); over pH 4.0, the Papp va were equal to the other HCAs [81,82].…”

“…These Papp values mean that less than 1% of each HCA was transported tow the receptor compartment [81][82][83]. A higher transport rate was only observed for F pH 4.0, for which the log Papp was −4.77 (Papp~17 × 10 −6 cm/s); over pH 4.0, the Papp va were equal to the other HCAs [81,82].…”

“…Transcellular passive diffusion is a process affected by the physicochemical pro ties of the drug, including the molecular weight (MW), partition coefficient (log P), d bution coefficient (log D), number of hydrogen bond donors (HBDs) and accep (HBAs), pKa, number of rotatable bonds (RBs) and polar surface area (PSA) [77,81,82 Based on the different physicochemical properties, some drug oral absorption predic rules are used in medicinal chemistry research and the pharmaceutical industry, suc the rules of Egan et al [85], Ghose et al [86], Lipinski et al [87], Muegge et al [88], O [89], Veber et al [90] and Zmuidinavicius et al [91], and the HCAs violate them in on more parameters (Figure 2). CGA violates all prediction rules, displaying the highest number of violations lowed by RA > CA > FA.…”