Disposition of everolimus in mdr1a-/1b- mice and after a pre-treatment of lapatinib in Swiss mice.
The aim of this study was to document the in vivo transport of everolimus (inhibitor of mTOR) by P-glycoprotein (P-gp), and to investigate the influence of lapatinib (inhibitor of P-gp) on everolimus disposition. Pharmacokinetics of everolimus (0.25mg/kg) has been investigated after oral administration in mdr1a-/1b- mice compared to the wild type. Also, everolimus pharmacokinetics was characterized after oral administration on Swiss mice either alone or after 2 days of pre-treatment of lapatinib (200mg/kg). The influence of lapatinib pre-treatment on intestinal P-gp expression was investigated by Western blot analysis. The non-compartimental analysis was performed using Winonlin professional version 4.1 software (Pharsight, Mountain View, CA). The areas under the plasma concentration-time curve (AUC) were compared using Bailer's method. A significant 1.3-fold increase of everolimus AUC observed in mdr1a-/1b- mice suggested that everolimus is transported in vivo by intestinal P-gp in mice. In addition, a 2.6-fold significant increase of everolimus AUC with lapatinib pre-treatment as compared with the everolimus alone group was noticed. The elimination half-life was comparable (t(1/2)=5.3h vs. t(1/2)=4h). A 38.5% significant decrease of P-gp expression was observed in duodenum segment in lapatinib pre-treated group as compared with control group. In conclusion, lapatinib enhanced everolimus absorption by decreasing intestinal P-gp expression. An inhibition of CYP 450 could not be excluded. These results confirm the necessity of a therapeutic monitoring of everolimus combined with an inhibitor of the P-gp and CYP 450 like lapatinib in a future anti-tumor treatment.
Chu
C
C
Laboratory of Pharmacology, Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier 94800, Villejuif, France. celinechu82@yahoo.fr
Abbara
C
C
Noël-Hudson
M S
MS
Thomas-Bourgneuf
L
L
Gonin
P
P
Farinotti
R
R
Bonhomme-Faivre
L
L
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000068338:Everolimus; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D000077341:Lapatinib; D051379:Mice; D018345:Mice, Knockout; D011799:Quinazolines / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013379:Substrate Specificity; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004077:Digoxin; D000068338:Everolimus; D000077341:Lapatinib; D011799:Quinazolines; D020123:Sirolimus; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3