DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 508

Pgp inhibitor) also results in a significant increase in TPT oral absorption. 56 Subse-
quently, TPT in combination with GF120918 demonstrated increased oral bioavail-
ability in the clinical setting. 57 Since TPT is not transported extensively by Pgp and
undergoes minimal CYP3A-catalyzed metabolism, 58 the pharmacokinetic interac-
tion observed between TPT and GF120918 could be ascribed predominantly to the
inhibition of the efflux transporter BCRP.
Other than limiting drug entry into the body, BCRP also restricts exposure to di-
etary carcinogens such as 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhlP).
Pharmacokinetic studies by van Herwaarden et al. 59 demonstrated that at a dose of 1
mg/kg [ 14 C]PhIP, the AUC of oral and intravenous administration was 2.9- and 2.2-
fold higher in Bcrp knockout mice than in wild-type mice, respectively. In mice with
cannulated gallbladders, both biliary and direct intestinal secretion of [ 14 C]PhIP were
greatly reduced in Bcrp knockout mice compared with wild-type mice. The data sug-
gest that Bcrp effectively restricts the exposure of mice to ingested PhIP by decreasing
its absorption from the small intestine and increasing biliary and intestinal secre-
tion. Since PhIP is the most abundant heterocyclic amine present in various protein-
containing foods, BCRP/bcrp1 is believed to play an important role in protection from
the toxicity of normal food constituents. The importance of BCRP as a detoxification
efflux transporter in the gut was also highlighted by Jonker et al., 55 who found that Bcrp
knockout mice are prone to developing phototoxic lesions on light-exposed areas of the
skin when fed a diet containing large amounts of chlorophyll. Further studies showed
that Bcrp efficiently limits the uptake of chlorophyll-breakdown product pheophor-
bide a, and the deficiency of Bcrp increases the exposure of mice to pheophorbide a,
leading to the high risk of protoporphyria and diet-dependent phototoxicity.

16.4.5. Transporters Localized on the Basolateral Membrane of Enterocytes

Little is known about the transport process occurring at the basolateral membrane
of the intestinal epithelium. Some functional studies provide strong evidence for
the existence of basolateral peptide transporters which are distinguishable from
PepT1 60 , 61 ; however, these putative transporters have not yet been cloned. MRP1 is
expressed primarily at the basolateral domain of the crypt cells in mouse and human
small intestine. 16 In vitro studies showed that MRP1 can efflux a variety of com-
pounds, including daunomycin 62 but and vincristine, 63 but its role in drug transport

in the intestine has not yet been clearly demonstrated.

16.5. FUNCTIONAL MODULATION OF INTESTINAL TRANSPORTERS
TO OPTIMIZE ORAL ABSORPTION OF DRUGS

In view of the importance of intestinal transporters in the absorption of certain drugs,
tremendous efforts have been made to identify chemical inhibitors of secretory
transporters, hoping to knock down the efflux activities of these gatekeepers,
thereby increasing the bioavailability of some poorly absorbed drugs. Up to now,