Gastrointestinal Absorption Kinetics Of Composition Compatibilities From Radix Aconiti Lateralis Preparata And Rhizoma Zingiberis.

AimsTo investigate the characteristics of gastrointestinal absorption kinetics of composition compatibilities from Radix Aconiti Lateralis Preparata (RALP) and Rhizoma Zingiberis (RZ), initially explore absorptive mechanism of total alkaloids from RALP (TA) in gastrointestine, and finally set up a method for gastrointestinal absorption kinetics for composition compatibilities of traditional Chinese medicinals (GAKTCM).MethodsAverage absorption rates (AARs) of composition compatibilities from RALP and RZ in stomach was studied by in situ stomach perfusion in rats in vivo and AAR in small intestine was studied also with rats by the similar method in small intestine in vivo. Based on the results, the kinetic equations of aconitine (AC), mesaconitine (MA), and hypaconitine (HA), which are components of TA, in gastrointestinal absorption were created and related kinetic parameters were calculated. The method of in vitro reversal intestinal sac was applied to study different AARs of TA in different places in small intestine, in different concentrations, or when in combination with P-glucoprotein (P-gp) inhibitor to initially analyze the absorptive mechanism of TA in gastrointestine.Results1. AARs of AC, MA, and HA in stomach in vivo had no difference when TA was given alone or in combination with RZ (p>0.05). However, the AARs of AC, MA, and HA in stomach were tend to decrease when TA was combined with the volatile oil of Rhizoma Zingiberis (OVRZ) (1:1) or combined with aqueous extract of Rhizoma Zingiberis (AERZ) (2:1). The results indicated that OVRZ and AERZ had a tendency to restrain absorption of AC, MA, and HA in stomach, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.2. By applying both techniques of in situ small intestine perfusion in vivo and reversal intestinal sac in vitro, the absorptions of AC, MA, and HA in intestine were studied when TA was given to rats singly, in combination with OVRZ or AERZ. The results showed first-order absorption kinetics of t all of the three main components of TA, exactly AC, MA, and HA.Both Ka and T1/2 were showed no significantly difference when TA was given to rats singley, or in combination with OVRZ and AERZ in ratio mentioned above (p>0.05) However, there was a tendency that Ka was decreased and simultaneously T1/2 was prolonged for all of AC, MA, and HA by compatibility. The results indicated that OVRZ and AERZ had a tendency to restrain intestinal absorption of AC, MA, and HA, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.AARs of AC, MA, and HA in jejunum, ileum, and colon were not influenced by drug concentration. The three alkaloids were probably absorbed by passive diffusion. AC, MA, and HA could be absorbed in jejunum, ileum, and colon, in which the AARs in jejunum and ileum were similar and AARs in colon was relatively lower than that in jejunum and ileum. The results indicated that the main absorptive place for AC, MA, and HA, diester alkaloids of aconitum, is small intestine, exactly jejunum and ileum.3. By applying P-gp in in vitro reversal intestine sac test, it was found that the AARs of AC, MA, and HA in jejunum, ileum, and colon were not significantly different between non-P-gp test and P-gp test (p>0.05), which indicated that none of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.Conclusions:The absorptions of TA components, exactly AC, MA, and HA, belongs to first order absorption kinetics. When TA is combined with compositions of RZ in corresponding ratios, there is a tendency that both Ka and AARs in stomach can be decreased in contrast to increase of T1/2. AARs of AC, MA, and HA in jejunum, ileum. and colon is not influenced by drug concentration and the absorptive mechanism may refers to passive diffusion. Jejunum and ileum are main places for absorption. None of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we devoted to set up the method and technology for GAKTCM and finally solved several problems as following:(1) We proposed the hypothesis of GAKTCM. (2) The key parts on the study of GAKTCM were concluded. (3) By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we got the related kinetic parameters and initially reveal the law of reducing toxicity in compositon compatibility of RALP and RZ.