MULTIDRUG RESISTANCE PROTEIN: P-GLYCOPROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 243

of ATP binding affinity showed only small changes upon drug binding. 83 Senior et al.
proposed that transport is driven by relaxation of a high-energy intermediate formed
during ATP hydrolysis, which thus provides the power stroke. 79 One molecule of ATP
was proposed to drive the transport of one drug molecule. Sauna and Ambudkar have
proposed an alternative model in which two molecules of ATP are hydrolyzed per
cycle. 185 In this model, drug and ATP binding do not influence each other: hydrolysis
of one ATP molecule drives drug transport, and hydrolysis of a second ATP molecule
resets the transporter. This model is also unsatisfactory. There has been no independent
verification of the proposed requirement for two rounds of ATP hydrolysis per drug
molecule transported. Sauna et al. reported that Pgps with mutations in the Walker
B Glu residues (E556Q and E1201Q) failed to undergo the second round of ATP
hydrolysis required to reset the transport cycle. 186 However, this was contradicted
by Senior and co-workers, who found that these mutants could undergo multiple
catalytic turnovers. Rapid kinetic studies that dissect out various steps in the transport
cycle, and define their kinetic and thermodynamic constants, may be required to fully
understand the mechanism of action of Pgp.
10.14. ROLE OF P-GLYCOPROTEIN IN DRUG THERAPY
Pgp substrates include many drugs that are used in the treatment of common human
diseases. The protein consequently plays a central role in drug absorption and dispo-
sition in vivo and is an important determinant in the pharmacokinetic profile of many
drugs and ultimately, the clinical response. 187 , 188 Pgp substrates include anticancer
drugs, HIV protease inhibitors, analgesics, calcium channel blockers, immunosup-
pressive agents, cardiac glycosides, antihelminthics, antibiotics, and H 2 -receptor an-
tagonists, to name just a few (see Table 10.1).
High levels of Pgp are found in the luminal membrane of the capillary endothelial
cells, where it immediately pumps drugs back into the blood. The presence of Pgp
strongly reduces the brain accumulation of many different drugs, and in knockout
mice, penetration of substrates into the brain is increased 10- to 100-fold. Pgp prevents
the penetration of HIV protease inhibitors into the brain, limiting treatment efficacy.
Anticancer drugs directed to brain tumors are also prevented from reaching their
desired site of action.
Pgp appears to be a major player in limiting absorption of drugs from the in-
testinal lumen. Studies in knockout mice showed that the bioavailability of orally
administered paclitaxel, a drug known for its poor solubility, increased from 11% to
35% in animals lacking Pgp. 189 Paclitaxel and other drugs are also excreted directly
from the blood circulation into the intestinal lumen. However, not all Pgp substrates
show compromised drug absorption. For example, digoxin, HIV protease inhibitors,
verapamil, and quinidine all show high oral bioavailability despite being good Pgp
substrates. 187 Thus, Pgp may not be as quantitatively important as first thought in
drug absorption. It is possible that high drug concentrations in the intestinal lumen
saturate the transporter; as well, Pgp-mediated efflux may have a limited effect on
bioavailability if passive diffusion rates are high. Because of the increased likelihood