excretion was not markedly different in wt and Mdr1a(-/-) mice. After IV
administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder,
11% of the dose was recovered within 90 min in the intestinal contents of wt
mice while less than 3% was recovered in Mdr1a(-/-) mice. All these data
clearly suggest that P-gp limits the oral uptake of paclitaxel and mediates direct
excretion of the drug from the systemic circulation into the intestinal lumen.
In general, the influence of efflux transporters on the intestinal drug
absorption is significant for the substrates with either low solubility (Wu and
Benet, 2005) or low permeability with high affinity to efflux transporters
(Ogihara et al., 2006). For a substrate with low permeability and high affinity,
efflux transporter may contribute more to the membrane clearance (Vmax/Km)
than the passive diffusion, and thus the changes in the efflux activity may
significantly alter their intestinal absorption rate. After oral administration of
½^3 Hvinblastine, a P-gp substrate with low permeability and high affinity, to
mice, the maximum concentration (Cmax)andtheAUC0–24 hin Mdr1a/1b (-/-)
mice were 1.5 times greater than those in wild type mice, whereas these
parameters were not significantly different between the two strains in the case
of½^3 Hverapamil, a P-gp substrate with high permeability and low affinity
(Ogihara et al., 2006). A low solubility drug, whether it is high or low
permeable, tends to have low concentrations coming into enterocytes and less
chance to saturate the efflux transporters. Therefore, the efflux transporters
are likely to affect the absorption rate and oral bioavailability (Weller et al.,
1993).
Besides P-gp, other efflux pumps such as BCRP can affect drug absorption.
Pretreatment of wt mice with gefitinib (Iressa), an oral epidermal growth factor
receptor tyrosine kinase inhibitor, increased oral absorption and decreased
systemic clearance of topotecan (a substrate for both P-gp and BCRP). Gefitinib
inhibited the efflux of BCRP and MDR1 substrates and restored vincristine
sensitivity in MDR1-expressing cells. Although gefitinib inhibited BCRP more
potently than MDR1 (10-fold), the inhibition of both transporters occurred at
clinically relevant concentrations (e.g., 1–5mM) (Leggas et al., 2006).
Uptake transporter prodrug substrates have been used to improve drug
absorption through GI tract. The most successful example is an antiviral
prodrug valacyclovir, which shows oral bioavailability three to five times
greater than its parent drug acyclovir (Weller et al., 1993). The increased oral
bioavailability is attributed to PEPT1-mediated absorption, which was
demonstrated by in situ rat perfusion model, Caco-2 cells, and PEPT1-
transfected CHO cells (Balimane et al., 1998).
6.2.2 Transporters in Drug Distribution
Transporters also contribute to the drug distribution in certain tissues. Most
statins are taken up into the hepatocytes by OATP, excreted into the bile by
efflux transporters, and reabsorbed in the intestine, thereby effectively
undergoing enterohepatic circulation and maintaining high concentrations in
148 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS