In vitro activation of irinotecan to SN-38 by human liver and intestine.
BACKGROUND
Irinotecan (CPT-11) is hydrolyzed by carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and hepatic activation. MATERNALS AND METHODS: Irinotecan was incubated with S9 fractions of human liver and intestinal tissues and the specific activity was determined based on the formation rate of SN-38.


RESULTS
Irinotecan was hydrolyzed to SN-38 by hepatic and intestinal S9 fractions with mean (+/- SD) specific activities (pmoles/min/mg) of: liver (8.57 +/- 10.4, n = 8), duodenum (5.06 +/- 3.7, n = 4), jejunum (6.44 +/- 2.8, n = 5), ileum (4.81 +/- 2.4, n = 5), colon (1.93 +/- 1.5, n = 6) and rectum (0.82, n = 1). When incubated with S9 fractions obtained from tumor tissues, there appeared to be a decrease in SN-38 formation compared to matched normal liver and colon tissues.


CONCLUSIONS
Irinotecan undergoes conversion to its active metabolite in human intestinal S9 fractions and there is variability in the extent of SN-38 formation. The localized intestinal activation of irinotecan to SN-38 may provide a rationale for the development of oral irinotecan for gastrointestinal malignancies but could also cause mucosal damage leading to toxicity.
Ahmed
F
F
Department of Pharmacology, Robert Wood Johnson Medical School, New Jersey, USA.
Vyas
V
V
Cornfield
A
A
Goodin
S
S
Ravikumar
T S
TS
Rubin
E H
EH
Gupta
E
E
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007082:Ileum / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism*; D000077146:Irinotecan; D007583:Jejunum / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009928:Organ Specificity; D011355:Prodrugs / Q000493:pharmacokinetics*; D012007:Rectum / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D011355:Prodrugs; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin