Biomedical Engineering Reference
In-Depth Information
lesterases CES1 and CES2, into the active metabolite hydroxycamp-
tothecin or SN-38, which is approximately 1,000 times more potent
than the parent drug [2]. Irinotecan is also oxidized by the cyto-
chrome P450 (CYP) 3A4 to two metabolites - APC (7-ethyl-10-[4-N-
(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin)
and NPC (7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamp-
tothecin). Of these, APC is a major oxidative metabolite and is inac-
tive, however NPC can be hydrolyzed by CES to SN-38. SN-38 itself is
further glucuronidated in the liver and intestine to form the inactive
SN-38 glucuronide (SN-38G). SN-38G is excreted in the small intes-
tine via bile where it can be deconjugated back to SN-38 in the gut
and intestine via the action of bacterial
β
-glucuronidase enzymes.
SN-38 may be conjugated to SN-38G again after reabsorption into the
intestinal tissues. The fate of irinotecan is also affected by the cyto-
chrome P450 enzyme system, primarily CYP3A4, which produces an
inactive form of irinotecan, the organic anion transporting polypep-
tide c (OATP1B1) which transports SN-38 from the plasma into the
liver, as well as the adenosine triphosphate-binding cassette (ABC)
transporter system that mediates drug efflux [2-7,9,10,12-14].
Irinotecan exerts its chemotherapeutic effects by interacting
with the enzyme topoisomerase I and inhibiting its function
[2-7,10,15]. Topoisomerase I is an enzyme in the cell nucleus that
regulates DNA topology and facilitates nuclear processes such as
DNA replication, recombination, and repair [6,10,15]. During these
processes, topisomerase I relieves torsional strain in DNA by inducing
reversible single-strand breaks, allowing single DNA strands to
pass through the break. The 3
′
-DNA terminus of the broken DNA
strands binds covalently with the topoisomerase enzyme to form
a catalytic intermediate called a cleavable complex. After the DNA
is sufficiently relaxed and the strand passage reaction is complete,
DNA topoisomerase I reattaches the broken DNA strands to form
the chemically unaltered topoisomers that allows transcription to
proceed. Irinotecan and its active metabolite SN-38 binds to the
topoisomerase I-DNA complex and prevents religation of these
single-strand breaks, thus stabilizing the DNA-topoisomerase I
complex in the cleaved DNA form, leading to breaks in both DNA
chains. As a result, DNA damage is not efficiently repaired, ultimately
leading to DNA fragmentation and cell death [2-7,10,15]. The main
toxicities associated with irinotecan therapy are myleosuppression
and diarrhea [2-10,12,16-19]. Myelosuppression is linked to
