title: Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression.
abstract: Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. 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 postpartum 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 the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. 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 21days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, 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.
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. Electronic address: peterk.hoffmann@novartis.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Beckman
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: McLean
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Jing-He
authors.initials: JH
authors.lastname: Yan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000375:Aging; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007583:Jejunum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014018:Tissue Distribution; D018675:Toxicity Tests; D000092502:Renin Inhibitors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D027361:Organic Anion Transporters; D000092502:Renin Inhibitors; C446481:aliskiren
keywords: Aliskiren; Exposure; Juvenile rat; MDR1; OATP; Toxicity