6.5.1 Oral Absorption
In humans, the role of transporters in drug absorption has been indirectly
shown by inhibition or induction studies. Drug-drug interactions due to P-gp-
mediated absorption are generally limited to some biopharmaceutics classifica-
tion system (BCS) class II and IV drugs, whereas there are minimal effects on
class I drugs with high solubility and high permeability due to the saturation
potential of P-gp at high therapeutic doses. Therefore, the importance of P-gp
in oral drug bioavailability, drug disposition in the liver, drug efflux in the
blood-brain barrier, and drug–drug interaction should be considered. This is
especially important for drugs with narrow therapeutic windows.
The classic example of digoxin-quinidine interaction was observed in early
1980s. Coadministered quinidine increased the absorption rate constant of
digoxin by 30%,Cmaxby 81%, and AUC by 77% in cardiac disease patients
(Pedersen et al., 1983). Only recently, the underlining mechanism of digoxin–
quinidine has been understood and has been attributed to intestinal P-gp (and
also liver and renal P-gp). Moreover, in healthy volunteers, oral coadministra-
tion of 100 mg talinolol, a P-gp substrate, increased the AUC0–6h and the
AUC0–72h of digoxin significantly by 18% and 23%, respectively, while
infusion of talinolol with oral digoxin had no significant effects on digoxin
pharmacokinetics. Digoxin did not affect the disposition of talinolol after both
oral and intravenous administration (Westphal et al., 2000b). Another study
showed that the talinolol (50 mg) AUC0–24handCmaxwere significantly increased
after administration of oral erythromycin at 2 g compared to placebo, while
the renal clearance of talinolol was unchanged in healthy volunteers. This
suggests that the increase in oral bioavailability of talinolol after concomitant
erythromycin is caused by increased intestinal net absorption due in turn to P-gp
inhibition by erythromycin (Schwarz et al., 2000).
P-gp expression level in humans directly affected oral digoxin and talinolol
absorption. Rifampin treatment (600 mg/day for 10 days) increased intestinal
P-gp content 3.5-fold, which correlated with the decreased AUC after oral
digoxin (1 mg) but not after intravenous digoxin (1 mg). Renal clearance and
half-life of digoxin were not altered by rifampin (Greiner et al., 1999a).
Similarly, the rifampin treatment was reported to result in increased expression
of duodenal P-gp content 4.2-fold and decreased AUC of intravenous and oral
talinolol (21% and 35%) in healthy volunteers, suggesting that rifampin
induces P-gp-mediated excretion of talinolol predominantly in the gut wall
(Westphal et al., 2000c). This implied that individual intestinal P-gp expression
difference could contribute to the individual pharmacokinetics variation of
digoxin and tanilolol.
For drugs with wide therapeutic index, the P-gp-mediated DDI may not be
clinically significant. In healthy volunteers, dexamethasone (widely included in
oncology antiemetic regimens) overall exposure was significantly increased by
24% by valspodar 400 mg, a P-gp modulator used as a chemotherapy adjunct.
However, this AUC increase is unlikely to be considered in a clinical setting
TRANSPORTERS IN DRUG–DRUG OR DRUG–FOOD INTERACTIONS 171