DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 509

the characterization of Pgp inhibitors represents the most successful example in this
research area and has generated a variety of specific and potent inhibitors, which can
be classified into three generations based on the time sequence of their identification
and the inhibitory mechanism. First-generation Pgp inhibitors include verapamil, cy-
closporin A, tamoxifen, and several calmodulin antagonists. Indeed, these inhibitors
are also Pgp substrates; therefore, the inhibitory mechanisms have been attributed to
competitive binding or transport. Owing to widespread availability (most of them are
commercially available), the first-generation Pgp inhibitors have been used exten-
sively to delineate the role of Pgp in drug transport across the cell membrane (e.g.,
drug-resistant tumor cells) or tissue barriers (e.g., intestine, liver, kidney, and BBB),
where Pgp protein resides. However, their clinical application for boosting drug
bioavailability is limited because the desired inhibitory potency on Pgp requires a high
blood concentration of inhibitors (at least three- to fivefold higher than their binding
affinity K m ), at which concentrations side effects will be evoked. Subsequently, the
second generation of Pgp inhibitors was synthesized with the goal of making the in-
hibitors more potent and less toxic. Representative second-generation Pgp inhibitors
include biricodar (VX-710) and PSC833 (valspodar), a nonimmunosupressive
derivative of cyclosporin D, which is 10- to 20-fold more potent than cyclosporin A
in its ability to inhibit Pgp. 64 Coadministration of the anticancer drug paclitaxel with
PSC833 resulted in a 10-fold increased oral bioavailability of paclitaxel in mice. 65
During the past several years, more potent and specific Pgp modulators, such as
LY335979 (zosuquidar), GF120918 (elacridar), XR9576 (tariquidar), and R101933
(laniquidar), have been developed as third-generation Pgp inhibitors. A mass balance
study demonstrated that concurrent administration of GF120918 results in almost
complete oral absorption of paclitaxel. 66 Using intestinal and vascular access-ported
(IVAP) rabbits, our laboratory found that in the presence of GF120918, the
bioavailability of upper small intestine-administered saquinavir increased twofold. 67
Using inhibitors of secretory transporters (e.g., Pgp) to boost the bioavailability
of some poorly absorbed drugs has generated some encouraging results. However, it
was noted recently that this strategy may be questionable for dual Pgp and CYP3A
substrates. Wu and Benet examined the influence of GF120918 on the disposition
of tacrolimus (a substrate for both Pgp and CYP3A) in isolated perfused rat liver
and found that tacrolimus AUC could be reduced significantly in the presence of Pgp
inhibitor. 68 In a clinical study, 69 patients receiving paclitaxel intravenous infusion with
concurrent oral administration of PSC833 showed increased plasma concentrations of
6

-hydroxypaclitaxel, a major metabolite of paclitaxel, compared to patients treated
with paclitaxel alone. These findings suggested that the Pgp inhibitor may sequester
its substrate in hepatocytes by inhibiting its biliary excretion, resulting in greater
metabolism by CYP3A.

16.6. CONCLUSIONS

Although our knowledge of physical pharmacy and advancements in manufactur-
ing technology have enabled the production of oral medicines with better absorption