Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 492

daunorubicin, idarubicin, paclitaxel, docetaxel, vincristine, vinblastine, topotecan,
etoposide and teniposide (Breedveld et al. 2006 ).
Furthermore, it has been proposed that intestinal P-gp would be functionally
linked to the cytochrome P-450 (more particularly the CYP3A4) and both com-
pounds would display complementary and synergistic roles in the pharmacokinetics
of drug absorption and elimination (Bardelmeijer et al. 2000a ) (Fig. 1a -3). The
P-gp activity would increase the residence of the drug in the gut and, that, would
enable more exposure to and more extensive metabolism by CYP3A4 (Kivisto et al.
2004 ). This fact is supported for at least, the following evidences: (i) the two proteins
are co-localized within the digestive tract and within enterocytes, (iii) they share
many of the same substrates and (iii) they are co-inducible in response to at least
some xenobiotics (Watkins 1997 ).
Apart from a poor membrane uptake, an extensive pre-systemic metabolism may
also be responsible of an important decrease of the drug bioavailability. This
pre-systemic metabolism in the gastrointestinal tract is related to the presence of the
following enzymes: (i) luminally secreted enzymes (i.e. pepsins, trypsin, chymotrypsin,
elastase and carboxypeptidase A/B), (ii) brush border membrane bound enzymes
such as various carboxypeptidases and aminopeptidases, and (iii) cytosolic enzymes.
In this context, cytochrome P450 (CYP) is the main oxidative drug metabolizing
enzyme system (Schellens et al. 2000 ). CYP consist of approximately 40 P450s,
among which the isoenzyme CYP3A4 is of special interest because it has a very
broad substrate specificity (van Waterschoot et al. 2009 ). This enzyme is the principal
CYP isoenzyme found in the enterocytes, where it serves as an important barrier
for xenobiotics to enter into the circulation (Bardelmeijer et al. 2000a ; Thummel
2007 ; Wacher et al. 2001 ). In fact, this enzyme is involved in the metabolism of at
least 50% of drugs (Lin and Lu 1998 ; Guengerich 1999 ). As indicated previously,
many anticancer agents are extensively metabolyzed by CYPs, such as the taxanes
paclitaxel and docetaxel, epipodophyllotoxins (etoposide, teniposide), vinca alkaloids
(vincristine, vinblastine, vindesine) and anthracyclines (doxorubicin, daunorubicin,
idarubicin) (Schellens et al. 2000 ). In addition, food constituents can profoundly
inhibit CYP3A, making significative variations in the bioavailability between patients
(van Herwaarden et al. 2007 ).
Regardless the mechanism of absorption and efflux mechanisms, the enterocyte
uptake leads to transport via blood capillaries and Peyer patches uptake through
intestinal lymphatics, from where drugs go to the blood via the mesenteric nodes
and the thoracic lymph duct (Fig. 1a -8). Lipophilic drugs can also gain access to
the intestinal lymphatic system via association with developing lipoproteins into
the enterocytes (Porter et al. 2007 ; Stremmel 1988 ).
The first-pass metabolism by the liver is the last obstacle for drug bioavailability
(Fig. 1a -7). This process refers to the loss of the drug due its biotransformation in
the liver before reaching the systemic circulation. In this organ the cytochrome
P-450 family of enzymes is the main responsible for the oxidation of drugs and
xenobiotics (Boobis and Davies 1984 ). The rate of drug elimination in the liver
depends on hepatic flow rate, intrinsic capacity of the enzymes to metabolize the
drug, and drug binding to plasma proteins (Agoram et al. 2001 ).