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Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation.

Abstract：

BACKGROUND:The intestinal uptake of the taxanes paclitaxel and docetaxel is seriously hampered by drug efflux through P-glycoprotein (P-gp) and drug metabolism via cytochrome P450 (CYP) 3A. The resulting low oral bioavailability can be boosted by co-administration of P-gp or CYP3A4 inhibitors. METHODS:Paclitaxel or docetaxel (10 mg/kg) was administered to CYP3A4-humanised mice after administration of the P-gp inhibitor elacridar (25 mg kg(-1)) and the CYP3A inhibitor ritonavir (12.5 mg kg(-1)). Plasma and brain concentrations of the taxanes were measured. RESULTS:Oral co-administration of the taxanes with elacridar increased plasma concentrations of paclitaxel (10.7-fold, P<0.001) and docetaxel (four-fold, P<0.001). Co-administration with ritonavir resulted in 2.5-fold (paclitaxel, P<0.001) and 7.3-fold (docetaxel, P<0.001) increases in plasma concentrations. Co-administration with both inhibitors simultaneously resulted in further increased plasma concentrations of paclitaxel (31.9-fold, P<0.001) and docetaxel (37.4-fold, P<0.001). Although boosting of orally applied taxanes with elacridar and ritonavir potentially increases brain accumulation of taxanes, we found that only brain concentrations, but not brain-to-plasma ratios, were increased after co-administration with both inhibitors. CONCLUSIONS:The oral availability of taxanes can be enhanced by co-administration with oral elacridar and ritonavir, without increasing the brain penetration of the taxanes.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Hendrikx JJ,Lagas JS,Wagenaar E,Rosing H,Schellens JH,Beijnen JH,Schinkel AH

doi

10.1038/bjc.2014.222

subject

Has Abstract

pub_date

2014-05-27 00:00:00

pages

2669-76

issue

11

eissn

0007-0920

issn

1532-1827

pii

bjc2014222

journal_volume

110

pub_type

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