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Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

Hoffmann, Peter and Mc Lean, Leeanne and Yan, Jing-He and Moulin, Pierre (2014) Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression. Toxicology and Applied Pharmacology 275 (2014) 36–43.

Abstract

BACKGROUND: The direct renin inhibitor aliskiren is approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population. METHODS: In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from post partum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of MDR1 and OATP mRNA in the intestine, liver kidney and brain. RESULTS: Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21 days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. CONCLUSIONS: Severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure following oral administration of aliskiren to juvenile rats.

Item Type: Article
Keywords: Aliskiren, juvenile rat, toxicity, exposure, MDR1, OATP
Date Deposited: 03 May 2016 23:45
Last Modified: 03 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/20113

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