Colon-Specific Delivery Release Of PL-Dextran Prodrung And Its Mechanism

AIM: (1) To establish IIPLC analytical method for determination of PL and PLH in biological samples and observe colon-specific delivery of PL- dextran prodrug in rats inflammatory bowel disease. (2)To study the mechanism of colonic delivery of PL-Dextran and provide scencific basis for seeking new drug to treat inflammatory bowel disease. METHODS: (1) PL and PLIJ in contents of the rat GI tract and plamsa samples were extracted with a mixture of methyl tert-butyl ether and pentane (V/V=213) .After the organic phase was seperated, dried and dissolved in methanol,the drug concentration was detected by HPLC.(2)PL prodrug and PL were respectively administrated to rat by oral gavage at the dose of 30 ii mol/kg.The distribution of PL, PLH in the contents and mucosa of different parts of rat GI tract between different interval,and the fluctuation of PL concentration in plasma were respectively determined by HPLC. Drug delivery index (DDJ) was calculated.(3)After the prodrug was incubated at 37~C with buffers of ?? different pH ,contents of different parts of rat 01 tract, buffers with dextranase and with culture medium containing Bacterium coli respectively, the release of PL and PLH from prodrug were determined by HPLC. RERULTS: (1)we selected C18 column(250mmX4.6mm) and a mobile phase consisting of 33% acetoni- true and 67% trisodium citrate buffer. The flow rate was lmL min1 and UV detection wavelength was 254 nm. The regression equation of standard curve Y0.06268+0.4747X (i =0.9999) was obtained to determine PL in contents of rat GI tract. The linear range was 0.15?.35 jl mol U? The regression equation of standard curve Y?.008689+0.7887X ( y =0.9999) was obtained to determine PLH in contents of rat GI tract. The linear range was 0.12-~ 4.97 ii mol F? The regression equation of standard curve Y=-0.08804+0.3756X (Y =0.9995) was obtained to determine PL in plasma. The linear range was 0.32 6.35 i~t mol F?The extraction recovery of PL and PLH ranged from 83% to 86%, the methodological recovery of PL and PLH from 98% to 103% and the RSDs of intra-day and inter-day from 1.0% to 2.1%. The limit of PL and PLH quantification were 0.037 14 and 0.05056 ii mol U?S/N3) respectively. (2)PL and PLH were mainly released in cecum and colon contents or mucosa after gastric administration of PL prodrug, while PL was mainly distributed in stomach,PSI and DSI contents or mucosa after free PL was administered at the same dosage.The peak concentration of PL in plasma determinated from prodrug was 0.66 1~ mol JJ1 and that from free PL was 2.34 i-~ mo> Li~ . The peak time of prodrug was 1.Oh and that of free PL was ?? O.5h.The DDI of prodrug was 6.464 in the cecal mucosa.(3)The amount of released PL was the highest in the cecum and colon contents; The release of active drug could increase at the p1-1 which was the most close to that of lower G1 tract; The dextranase and the Bacterium coli could facilitate the release of active drug. CONCLIJSION:(1)The method is accurate, simple, rapid, sensitive and good enough to be applied to study the pharmacokinetic of new preparation of PL as well as the PL and PL prodrug.(2)As the DDI of prodrug is relatively high, we could draw a conclusion that PL could be delivered to large intestine by synthesized PL prodrug .It appears that the P...