DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 507

with efflux ratios of 5.4, 9.7, and 4.8 in rat jejunum, ileum, and colon, respectively.
Moreover, the presence of quinidine in the diffusion buffer could markedly reduce
etoposide efflux ratio highlighting the critical role of intestinal Pgp in the absorp-
tion and secretion of etoposide. Diffusion studies using excised intestinal tissue have
proved useful in mechanistically characterizing the drug transport process, however,
kinetic parameters (e.g., permeability) are usually obtained at steady state. Therefore,
better in vitro-in vivo correlations (IVIVCs) are necessary for accurate prediction of
drug absorption and/or secretion in vivo.
Since the discovery of Pgp, a large number of in vitro and in vivo studies have
been carried out to assess its detoxification function as a secretory transporter. Pgp-
mediated transport reduces drug exposure by preventing the entry of xenobiotics into
the human body and/or facilitating their elimination out of body. However, intestinal
Pgp-mediated efflux may not play a significant role in oral bioavailability of certain
drugs even though they have been demonstrated to be typical substrates for Pgp at
the cell culture level. This is well demonstrated for high-permeability/high-solubility
drugs such as verapamil. 11 , 12 As discussed in Section provided that the clinical dose
is relatively high, high solubility and permeability will make simple diffusion [value
of P m C in equation (9)] the dominant factor in drug transport, eclipsing the effect of
Pgp-mediated efflux. Many pharmaceutical companies are now using several in vitro
methods (cell- or enzyme-based) to screen Pgp substrate at the early development
stage. However, the decision of discontinuing an in vitro-identified Pgp substrate for
late drug development must be made with great caution, since the very low concen-
trations used for in vitro studies results in readily detected Pgp function, and the role
of efflux transporter in the oral availability of certain drugs may not be substantial in
actual clinical practice. 47
Most Pgp-transported drugs are also substrates for phase I metabolic enzyme cy-
tochrome P450 (CYP) 3A4. The coexpression of these two proteins in the intestine
and the interplay between them complicates the demonstration of either protein's
contribution to drug absorption. It is now generally accepted that intestinal metabolic
enzymes and efflux transporters work coordinately as a detoxification system, result-
ing in the poor bioavailability of certain drugs. 48
16.4.4. BCRP-Mediated Secretory Transport
BCRP was cloned independently by several research groups from drug-resistant can-
cer cells 49 , 50 or placenta. 51 Unlike other ABC transporters, BCRP contains only
one membrane-spanning domain and one nucleotide-binding domain. Some avail-
able experimental evidence suggests that BCRP may function as a homodimer or
homotetramer, 52 − 54 so it is also called a half-transporter .
BCRP is expressed abundantly at the apical membrane of the small intestine and
colon epithelium, where it limits drug absorption and/or facilitates secretion back
into lumen. This has been well demonstrated by several animal and clinical studies.
Jonker et al. 55 compared the bioavailability of the anticancer drug topotecan (TPT, a
topoisomerase I inhibitor) in Bcrp knockout mice and found that the AUC of orally
administered TPT is about sixfold higher in Bcrp-deficient mice than in wild-type
mice. Chemically knocking down mice Bcrp function by its inhibitor GF120918 (also