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.
Highlights
Transmembrane transport plays critical roles for bioavailability of drugs
We found that vanillin could enhance the passive transport rate and absorption of drugs with a moderate oral bioavailability by increasing the permeability of the cell membrane
Benzaldehyde (50 μM) did not obviously affect the Papp values of the all four passive transport drugs from BL-AP. These results suggest that benzaldehyde could significantly enhance the passive diffusion of hydrophobic drugs (ACV and HTZ), which has the tendency to inhibit the active transport of P-gp
Summary
Transmembrane transport plays critical roles for bioavailability of drugs. It is known that the promotion of transmembrane transport could improve bioavailability and the efficacy of drugs. Despite the lipophilicity of a drug molecule as a rate-limiting factor for passive diffusion across biological membranes, how to improve the bioavailability of hydrophilic drugs had gained attention over the years. Some natural medicines had proved to promote the absorption of hydrophilic drugs such as “kaiqiao” medicine; the mechanism of absorption-promoting effects is less understood. “Kaiqiao” medicine, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa, which have been used for decades in East Asia, India, Africa, and Turkey. According to the theories of traditional Chinese medicine (TCM), the function of “kaiqiao” medicine is Benzaldehyde Promote Absorption by Disturb Cell-Membrane
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