Reference - Detail
| 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | LLC-GA5-CoL150(RCB0871) |