Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 494

Ftorafur ® (Kawata et al. 1984 ), 5-FU glucuronide (Guerquin-Kern et al. 2000 ), and
5¢-DFUR and capacitabine (Armstrong and Diasio 1980 ; Thorne et al. 2009 ).
All of these prodrugs were designed to overcome the rapid breakdown of 5-FU in
the gastrointestinal tract and its gut toxicity.
5-FP is activated to 5-fluorouracile by aldehyde oxidase; although, no improved
antitumor activity compared with 5-FU has been observed (Guo et al. 1995 ). In addi-
tion, aldehyde oxidase is widely distributed within the body and, thus, it would not
be an ideal candidate for the development of prodrugs (Murray et al. 1995 ). Ftorafur®
or Tegafur ® is a slow-releasing prodrug which is activated to 5-FU by cytosolic
thymidine phosphorylase and microsomal P450 (Ohashi et al. 2010 ; Takiuchi and
Ajani 1998 ), whereas 5-FU glucuronide is activated by b-glucuronidase (Guerquin-
Kern et al. 2000 ). Again, P450 and b-glucuronidase are also widely distributed and,
thus, the activation of the prodrug would also occur in nontumor tissues (Murray
et al. 1995 ). Probably, the most interesting 5-FU prodrug is capecitabine (Xeloda®)
which is a derivative of 5¢-deoxy-5-fluorouridine (5¢-DFUR) with a significantly
lower gastrointestinal toxicity. This prodrug, which is currently clinically used, is
sequentially activated into 5-FU by three enzymes, i.e., carboxylesterase, cytidine
deaminase, and thymidine phosphorylase (Miwa et al. 1998 ). This last enzyme is
up-regulated in breast, ovarian, colorectal, and gastric cancers (Cole et al. 1999 ).

3.2 P-Glycoprotein Inhibitors

Many anticancer drugs are substrates by P-gp. The inhibition of this efflux pump
has been a common strategy to overcome the low oral bioavailability of many anti-
cancer drugs. Inhibition of P-gp may be tackled by (i) co-administration of agents
known as P-gp substrates in order to act as inhibitors of the transporter, (ii) develop-
ment of novel agents that are non P-gp substrates, and (iii) design of formulations
that allow the drug to bypass efflux pump transport.
The first attempt to inhibit the activity of intestinal P-gp was the co-administration
of other substrates of this transporter. In this context, drugs such as verapamil
(Kruijtzer et al. 2002 ) or cyclosporine A (Demeule et al. 1999 ) were proposed. Both
compounds can compete with the drug of interest by P-gp, increasing the possibility
of drug absorption. However, due to the usually low binding affinities of these drugs
for the intestinal P-gp, large doses are required to be effective. As a consequence,
unacceptable toxicity events can be observed (Bansal et al. 2009a ; Benet et al.
2004 ). In addition, these P-gp inhibitors also show a concomitant inhibition of
cytochrome P-450 and, thus, pharmacokinetic interactions can occur (Bansal et al.
2009a ). In summary, co-administration of an anticancer drug and a non-selective
P-glycoprotein inhibitor resulted in decreased clearance and increased toxicity of
the treatment (Benet et al. 2004 ).
The second generation of P-gp inhibitors was initially developed to reverse mul-
tidrug resistance. Many of these compounds (i.e. the cyclosporin A analog valspodar)
were derivatives of the first generation, however, as the original compounds, these