Biomedical Engineering Reference
In-Depth Information
water-soluble analogues that had a favorable toxicity profile as well as
consistent antitumor activity [7]. The survival advantages associated
with irinotecan was the basis for full FDA approval of irinotecan as a
second-line therapy for patients with metastatic colorectal cancer in
September of 1998 although it has more recently been approved for
use as first-line treatment as well, and is often used in combination
with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab
[2,6,8-11,19].
The metabolism of irinotecan is summarized in Fig. 12.1.
Irinotecan is hydrolyzed in the liver and intestine by the carboxy-
Figure 12.1
The conversion of the irinotecan to the active metabolite,
7-ethyl-10-hydroxycamptothecin (SN-38) is catalyzed by
carboxyesterase (CES) 1 and 2. Prolonged levels of SN-38 in the
plasma leads to neutropenia. The inactivation of SN-38 to the
glucuronide form (SN-38G) is catalyzed by UGT1A1 and UGT1A9.
SN-38G is excreted in the bile, where its conversion back to SN-
38 is catalyzed by enteric bacterial ß-glucuronidase. Increased
levels of SN-38 in the intestine can lead to severe diarrhea.
Extrahepatic SN-38 is inactivated to SN-38G through a reaction
catalyzed by UGT1A1, UGT1A7, and UGT1A9. Cytochrome
P-450 (CYP) 3A4 and 3A5 catalyze the conversion of irinotecan
to the inactive metabolites 7-ethyl-10-[4-
-(5-aminopentanoic
acid)-1-piperidino] carbonyloxycamptothecin (APC) and
7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin
(NPC). Adenosine triphosphate-binding cassette (ABC) B1, C1,
C2, and G2 function catalyze the transport of irinotecan out of
the liver. Modified from [2,9].
N
