| RRC ID |
44567
|
| Author |
Tsukimoto M, Ohashi R, Torimoto N, Togo Y, Suzuki T, Maeda T, Kagawa Y.
|
| Title |
Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys.
|
| Journal |
Biopharm Drug Dispos
|
| Abstract |
Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.
|
| Volume |
36(1)
|
| Pages |
15-33
|
| Published |
2015-1-1
|
| DOI |
10.1002/bdd.1920
|
| PMID |
25264342
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily B / genetics*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP-Binding Cassette Sub-Family B Member 4
Amides / pharmacokinetics*
Animals
Antihypertensive Agents / pharmacokinetics*
Area Under Curve
Cyclosporine / administration & dosage
Cyclosporine / pharmacology
Dibenzocycloheptenes / pharmacology
Dose-Response Relationship, Drug
Drug Interactions
Fumarates / pharmacokinetics*
Humans
Macaca fascicularis
Male
Mice
Mice, Knockout
Quinolines / pharmacology
Species Specificity
|
| IF |
12.121
|
| Times Cited |
57
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Human and Animal Cells |
LLC-GA5-CoL150(RCB0871) |
