In Vitro Study On Mechanism Of Attenuation In Aconitum By Processing And Compatibility

For centuries, aconitum species have been widely used as a traditional medicinein Asia. Their pharmacological effects are mainly due to various alkaloids withproperties such as analgesic, anti-inflammatory, anti-epileptic activities. Diester typealkaloids are compounds with cardiotoxic and neurotoxic activities, which lead to anarrow therapeutic index. The improper use of aconitum may cause severeintoxication, thus it is important to study the method which can decrease toxicity andincrease effects. There are two main methods processing and combination to decreasetoxicity. There have been a lot of reports on the chemical analytical about theprocessing or combination of aconitum. But there were a few reports on theirbioavailability after oral administration.In the present study, we aimed to characterize the transcellular transport ofaconitum alkaloids using human colon carcinoma cell line Caco-2cells. Weinvestigated the absorption of raw aconitum and processed aconitum, Pappvalues ofthe six aconitum alkaloids were all more than1×10-6cm/s, confirming the processesof permeability were valid. The Pappvalues stable over the concentration range studied,demonstrating the existence of a passive diffusion for its transport across Caco-2cellmonolayers. For the differences of structure between monester type and diester typealkaloids, the more lipophilic diester type alkaloids were much more liable to acrossthe cells. The processing changes the content but not the ingredients of the alkaloids.For the Pappstabled over the concentration range, we concluded that processing didnot affect the absorption of aconitum alkaloids.We investigated the interaction between extract of aconitum alkaloids and waterextract of combination herbs, such as Glycyrrhiza uralensis, Zingiber officinale,Pinellia ternata, Schisandra chinensis, Fritillaria thunbergii. The results showed thatthe Pappchanged significantly with the presence of combination herbs. Glycyrrhiza uralensis, Zingiber officinale and Pinellia ternata decreased the absorption of theaconitum alkaloids, the effect of Pinellia ternata was maximum, which wascontradictory with “SHI BA FAN”. The presence of Schisandra chinensis andFritillaria thunbergii increased the absorption of aconitum alkaloids, the effect ofFritillaria thunbergii was more significant. Fritillaria thunbergii increased theabsorption of aconitum alkaloids accompany with decreased the secretion, result inthe increase of bioavailability.To find the mechanism on Fritillaria thunbergii and Fritillaria cirrhosa increasethe absorption of aconitum alkaloids, we investigated PE, PEN and SPE fromFritillaria thunbergii and Fritillaria cirrhosa, and BMA, BAC, BHA, MA, AC, HAfrom aconitum. We found that P-gp inhibitor verapamil and PE, PEN, SPE inhibit theexcretion of aconitum alkaloids significantly, which demonstrated BMA, BAC, BHA,MA, AC, HA are the substrate of P-gp. PE, PEN, SPE inhibited the excretion of P-gpsubstrate digoxin, which demonstrated PE, PEN, SPE are the inhibitor of P-gp, whichcan increase the absorption of P-gp substrate. The experiment revealed the interactionmechanism between Fritillaria thunbergii, Fritillaria cirrhosa with aconitum.