Microemulsion As A Drug-loaded System Promotes Intestinal Absorption Of Octreotide

Objective: In China, portal hypertension is a common disease with a high morbidity and mortality. Currently there is no ideal oral drug. It is well known that Octreotide is an effective drug for reducing portal hypertension. However, it can only be administrated by intravenously because of its low oral bioavailability. This paper firstly investigated the best intestinal segment for absorption of Octreotide, as well as prepared Octreotide microemulsions, aiming to evaluate whether the microemulsions could increase the absorption of Octreotide and improve the bioavailability. We hoped that it would provide a foundation of theoretical and experimental basis for the effectiveness and feasibility of oral agents of Octreotide.Methods1. The intestines of 24 SD male rats (200g) were isolated and esta- blished the intestinal loop model of rat in vivo. 2ml (200μg) of the Octreotide solution were added to the required intestinal lumen (duodenum, jejunum, ileum and colon). Blood (0.5ml) was collected 5min before administration and 20, 60, 120, 180, 220and300min after administration of the drug, respectively. We detected plasma concentration of Octreotide by HPLC-MS/MS. By comparing the differences of the pharmacokinetic parameters among the respective intestinal segments, we studied and determined the best site of absorption of Octreotide.2. Octreotide microemulsion was prepared with lecithin as surfactant, butanol as cosurfactant, isopropyl myristate as extra-oil and Octreotide solution as inner phase. Three different Octreotide microemulsions were obtained based on the proportion of surfactant, cosurfactant and extra-oil, which were 1.2:1:2,1.1:1:2,1:1:2.3. 30 SD male rats (200g) were divided into 5 groups, one group was injected with 20μg of Octreotide solution through the femoral vein, one group was given 200μg of Octreotide solution in jejunum,and the other three groups were gaved the above three prepared Octreotide microemulsions containing 200μg of octreotide into the jejunums after opening abdominal cavity, 0.5ml blood were taken 5min before and 20, 60, 120, 180, 220, 300min after administrating of the drug from the rats of each other 5 groups. We determined the plasma concentration of Octreotide by High Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrome- try ( HPLC–MS∕ MS ) , compared the pharmacokinetic parameters of each group, and calculated the absolute bioavailability according to F= (AUCpo×DOSEiv)/ (AUCiv×DOSEpo).Results1. Octreotide could be absorbed in all parts of the intestine. The AUCt values of duodenum, jejunum, ileum and colon were (1175±80.8) min×ng/ml, (2205.3±161.1) min×ng/ml, (1382±142.6) min×ng/ml, (1352.±127.3) min×ng/ml, respectively. However the absorption ability of the intestinal segments for Octreotide were different. The absorption of jejunum was significantly different compared with duodenum, ileum and colon (P <0.05), and was about 2 times that of the duodenum, and 1.5 times that of the jejunum and colon. There was not significantly different of the absorption every both of intestinal segments (P> 0.05).2. The bioavailabilities of Octreotide microemulsions were signi- ficantly different compared with the Octreotide solution (P<0.05). The absolute bioavailability of Octreotide microemulsion groups were (14.68±3.06)%, (13.58±2.77)% and (12.04±2.15)% respectively, and compared with Octreotide solution, the maximum values increased 7.88 times.3. There was not significantly different among bioavailabilities of Octreotide microemulsion groups (P> 0.05).Conclusions1. Octreotide can be absorbed in all parts of the intestine, but the abs- orption ability is different. The absorption in jejunum is significantly better than the other intestinal segments. The jejunum is the best absorption site for Octreotide.2. Octreotide microemulsion can promote absorption of Octreotide in jejunum and improve its bioavailability significantly, showing that microemulsion as a drug-loaded system has an effect on intestinal absorption of peptides and it is a better transport carrier.