PMID- 25264342
OWN - NLM
STAT- MEDLINE
DCOM- 20150909
LR  - 20231213
IS  - 1099-081X (Electronic)
IS  - 0142-2782 (Linking)
VI  - 36
IP  - 1
DP  - 2015 Jan
TI  - Effects of the inhibition of intestinal P-glycoprotein on aliskiren 
      pharmacokinetics in cynomolgus monkeys.
PG  - 15-33
LID - 10.1002/bdd.1920 [doi]
AB  - 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.
CI  - Copyright (c) 2014 John Wiley & Sons, Ltd.
FAU - Tsukimoto, Mikiko
AU  - Tsukimoto M
AD  - Discovery Screening Center, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, 
      Japan; Department of Clinical Pharmaceutics, School of Pharmaceutical Sciences, 
      University of Shizuoka, Suruga, Shizuoka, Japan.
FAU - Ohashi, Rikiya
AU  - Ohashi R
FAU - Torimoto, Nao
AU  - Torimoto N
FAU - Togo, Yoko
AU  - Togo Y
FAU - Suzuki, Takashi
AU  - Suzuki T
FAU - Maeda, Toshio
AU  - Maeda T
FAU - Kagawa, Yoshiyuki
AU  - Kagawa Y
LA  - eng
PT  - Journal Article
DEP - 20141031
PL  - England
TA  - Biopharm Drug Dispos
JT  - Biopharmaceutics & drug disposition
JID - 7911226
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Amides)
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Dibenzocycloheptenes)
RN  - 0 (Fumarates)
RN  - 0 (Quinolines)
RN  - 502FWN4Q32 (aliskiren)
RN  - 813AGY3126 (zosuquidar trihydrochloride)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 9EI49ZU76O (multidrug resistance protein 3)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/*genetics
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists & inhibitors
MH  - Amides/*pharmacokinetics
MH  - Animals
MH  - Antihypertensive Agents/*pharmacokinetics
MH  - Area Under Curve
MH  - Cyclosporine/administration & dosage/pharmacology
MH  - Dibenzocycloheptenes/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Fumarates/*pharmacokinetics
MH  - Humans
MH  - Macaca fascicularis
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Quinolines/pharmacology
MH  - Species Specificity
MH  - ATP-Binding Cassette Sub-Family B Member 4
OTO - NOTNLM
OT  - aliskiren
OT  - cynomolgus monkeys
OT  - inhibition
OT  - intestine; P-gp
OT  - pharmacokinetics
EDAT- 2014/09/30 06:00
MHDA- 2015/09/10 06:00
CRDT- 2014/09/30 06:00
PHST- 2014/06/15 00:00 [received]
PHST- 2014/09/08 00:00 [revised]
PHST- 2014/09/21 00:00 [accepted]
PHST- 2014/09/30 06:00 [entrez]
PHST- 2014/09/30 06:00 [pubmed]
PHST- 2015/09/10 06:00 [medline]
AID - 10.1002/bdd.1920 [doi]
PST - ppublish
SO  - Biopharm Drug Dispos. 2015 Jan;36(1):15-33. doi: 10.1002/bdd.1920. Epub 2014 Oct 
      31.