Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation.
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.
1] Department of Pharmacy and Pharmacology, Slotervaart Hospital, PO 90440, 1006 BK Amsterdam, The Netherlands [2] Division of Molecular Oncology, The Netherlands Cancer Institute, PO 90203, 1006 BE Amsterdam, The Netherlands.
J J M A
JJ
Hendrikx
Department of Pharmacy and Pharmacology, Slotervaart Hospital, PO 90440, 1006 BK Amsterdam, The Netherlands.
J S
JS
Lagas
Division of Molecular Oncology, The Netherlands Cancer Institute, PO 90203, 1006 BE Amsterdam, The Netherlands.
E
E
Wagenaar
Department of Pharmacy and Pharmacology, Slotervaart Hospital, PO 90440, 1006 BK Amsterdam, The Netherlands.
H
H
Rosing
1] Department of Clinical Pharmacology, The Netherlands Cancer Institute, PO 90203, 1006 BE Amsterdam, The Netherlands [2] Department of Pharmaceutical Sciences, Utrecht University, PO 80082, 3508 TB Utrecht, The Netherlands.
J H M
JH
Schellens
1] Department of Pharmacy and Pharmacology, Slotervaart Hospital, PO 90440, 1006 BK Amsterdam, The Netherlands [2] Department of Pharmaceutical Sciences, Utrecht University, PO 80082, 3508 TB Utrecht, The Netherlands.
J H
JH
Beijnen
Division of Molecular Oncology, The Netherlands Cancer Institute, PO 90203, 1006 BE Amsterdam, The Netherlands.
A H
AH
Schinkel
D000166:Acridines / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D000077143:Docetaxel; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017239:Paclitaxel / Q000008:administration & dosage; D019438:Ritonavir / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D014018:Tissue Distribution
D000166:Acridines; D043823:Taxoids; D044005:Tetrahydroisoquinolines; D000077143:Docetaxel; C083501:Elacridar; D019438:Ritonavir; D017239:Paclitaxel