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. 2021 May 28:12:663743.
doi: 10.3389/fphar.2021.663743. eCollection 2021.

Benzaldehyde, A New Absorption Promoter, Accelerating Absorption on Low Bioavailability Drugs Through Membrane Permeability

Wen Wen  1   2 , Jie Luo  1   2 , Ping Li  1   2 , Wenge Huang  1   2 , Ping Wang  1   2 , Shijun Xu  1   2
Affiliations

Benzaldehyde, A New Absorption Promoter, Accelerating Absorption on Low Bioavailability Drugs Through Membrane Permeability

Wen Wen et al. Front Pharmacol. .

Abstract

Styrax, one of the most famous folk medicines, is a necessary medicine in formulas to help other drugs reach the focal zone and maximize the effectiveness, the mechanism that promotes absorption is not clear yet. This study was carried out to investigate the absorption-promoting effects and the mechanism of benzaldehyde, a key active compound of styrax, on the diffusion rates of drugs with different oral bioavailability. Caco-2 transport experiments were used to investigate the transport rate. Molecular Dynamics Simulation analysis and fluorescence-anisotropy measurements were used to explore the underlying mechanism of absorption-promoting. Validation test in vivo was carried out to reveal the absorption-promoting effects of benzaldehyde on high hydrophilicity drugs. Our data indicated that benzaldehyde(50 μM) elevated the cumulative quantity of passively diffusion drugs with high hydrophilicity such as acyclovir and hydrochlorothiazide. MD and membrane fluidity data explained that benzaldehyde can loosen the structure of the lipid bilayer. The validation tests showed that benzaldehyde (140 mg/kg) remarkably increased the Cmax and AUC0-6 of acyclovir and hydrochlorothiazide in vivo. These present studies suggested that benzaldehyde can promote the absorption of drugs with a lower oral bioavailability through disturbing the integrity of lipid bilayer enhanced membrane permeability.

Keywords: absorption-promoting; benzaldehyde; drug interaction; membrane permeability; transmembrane transport.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

GRAPHICAL ABSTRACT
GRAPHICAL ABSTRACT
The changes in the fluorescence anisotropy of TMA-DPH in Caco-2 cells with different concentrations of benzaldehyde molecules. (●) HBSS, (■) 25 μM benzaldehyde, (▲) 100 μM benzaldehyde. Data are shown as the mean ± SD.
FIGURE 1
FIGURE 1
Effect of benzaldehyde on transmembrane transport study. Concentration of benzaldehyde molecules. From the left to right were the accumulation and Papp of marker drugs across AP-BL and BL-AP, the efflux of marker drugs. (A) VIN; (B) ACV; (C) HTZ; (D) PRO; and (E) CAR. *p < 0.05 meant compared to the control group (no benzaldehyde). Data are shown as the mean ± SD.
FIGURE 2
FIGURE 2
All atoms-MD simulation analysis of atom-bead mapping scheme of different concentration benzaldehyde on membrane structure. (A–C) The final simulation snapshots of the benzaldehyde molecules passing through the POPC membrane from the X, Y, and Z axis; (D) mean square displacement of the bilayer; (E) order parameter of alkyl chain C21–C216 and C31–C318 of POPC molecule; (F) area per lipid of the membrane.
FIGURE 3
FIGURE 3
The changes in the fluorescence anisotropy of TMA-DPH in Caco-2 cells with different concentrations of benzaldehyde molecules. (●) HBSS, (■) 25 μM benzaldehyde, (▲) 100 μM benzaldehyde. Data are shown as the mean ± SD.
FIGURE 4
FIGURE 4
The absorption-promoting effects of benzaldehyde for acyclovir (ACV) and hydrochlorothiazide (HTZ) in vivo. (A) Mean plasma concentration–time profile of acyclovir with or without benzaldehyde. (●) Control group (acyclovir 5 mg/kg), (■) 140 mg/kg benzaldehyde (acyclovir 5 mg/kg). (B) Mean plasma concentration–time profile of hydrochlorothiazide with or without benzaldehyde. (●) Control group (hydrochlorothiazide 17 mg/kg), (■) 140 mg/kg benzaldehyde (hydrochlorothiazide 17 mg/kg).
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