CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 752

700

600

500

WT+CsA

400

300

KO

200

100

WT

0

0 2 4 6 8 10 12 14 16

Time (h)

(a)

0.30

+ CsA (n = 9)

No CsA (n = 5)

0.20

0.10

0.00

0 6 12 18 24 30 36

Time (h)

(b)

FIGURE 24.1. ( a ) Coadministration of oral paclitaxel and cyclosporin A (CsA) in wild-type
(WT) mice resulted in a significant increase in the area under the curve (AUC) of paclitaxel in
plasma. The effect was even greater than the AUC of paclitaxel when given to Pgp-deficient
mdr1a/b knockout (KO) mice. The results indicate that Pgp effectively prevents oral uptake of
paclitaxel from the gut. CsA may also have inhibited CYP3A to explain the additional increase
in the AUC compared with the experiment in KO mice. ( b ) Coadministration of oral paclitaxel
and cyclosporin A in patients with advanced cancer resulted in a significant increase in the
AUC of paclitaxel in plasma. These results are the clinical proof of the concept that inhibition
of Pgp (and possibly also CYP3A in the gut epithelium) results in a significant increase in the
uptake of paclitaxel from the gut, leading to a significant increase in the systemic exposure to
paclitaxel. [( a ) From ref. 60, with permission; ( b ) from ref. 162, with permission.]