[Synthesis of colon-specific prodrug of indomethacin and its inhibitory effect on liver metastasis from colon cancer].
OBJECTIVE
To develop a colon-specific prodrug of Indomethacin microbially triggered, carry out in vitro/in vivo evaluation of drug release, and appraise its inhibitory effect on liver metastasis from colon cancer.


METHODS
Indomethacin prodrugs were synthesized and characterized by FTIR and NMR, and dissolution test simulating gastrointestinal tract was employed to screen the colon-specific prodrug. Then, the pharmacokinetic profile of portal vein and peripheral blood in Sprague-Dawley rats was studied. Lastly, the inhibitory effect on liver metastasis from colon cancer in nude mice was observed.


RESULTS
The chemical structure characterized by FTIR and NMR demonstrated that six kinds of indomethacin-block-amylose with different drug loading (IDM-AM-1-6) were synthesized, among which IDM-AM-3 was degraded 1.3%, 9.3% and 95.3%, respectively, in simulated gastric fluid for 4 h, small intestine for 6 h, and colon for 36 h. The pharmacokinetic test of IDM-AM-3 showed that absorption was delayed significantly (P < 0.01), peak time [(11.35 + or - 2.45) h], elimination half-life [(16.74 + or - 4.04) h] and mean residence time [(22.27 + or - 0.52) h] were significantly prolonged (P < 0.01), as well as peak serum concentrations [(9.69 + or - 2.40) mg/L] and AUC(0-t) [(236.7 + or - 13.1) mg x L(-1) x h] were decreased markedly (P < 0.01) as compared with those of IDM regarding to portal vein. Additionally, its AUC(0-t) in peripheral blood was remarkably lower than that in Portal vein (P < 0.01). The tumor suppression observation showed that it could remarkably reduce the number of liver metastases in contrast to IDM (P < 0.05).


CONCLUSIONS
Colon-specific IDM-AM-3 possesses advantage of sustained release in portal vein providing some experimental basis for colon-specific delivery system applied to sustained release in the portal vein.
Peng
Ning-fu
NF
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Yang
Li-qun
LQ
Chen
Ru-fu
RF
Cai
Xiang
X
Li
Le-qun
LQ
Li
Zhi-hua
ZH
Zhou
Quan-bo
QB
Zhou
Jia-jia
JJ
Jiang
Zhi-peng
ZP
D000688:Amylose / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D019073:HT29 Cells; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D003692:Delayed-Action Preparations; D011355:Prodrugs; D000688:Amylose; D007213:Indomethacin