title: Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.
abstract: 1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Jimmy
authors.initials: J
authors.lastname: Flarakos
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Yancy
authors.initials: Y
authors.lastname: Du
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Timothy
authors.initials: T
authors.lastname: Bedman
authors.affiliation: b Department of Clinical Sciences .
authors.forename: Qusai
authors.initials: Q
authors.lastname: Al-Share
authors.affiliation: c Department of Drug Safety & Epidemiology Clinical Development , Novartis Institutes for Biomedical Research , Novartis Pharma, East Hanover, NJ , USA , and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.affiliation: d Department of Clinical Pharmacology , Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.affiliation: b Department of Clinical Sciences .
authors.forename: Diego
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Einolf
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: Su-Er
authors.initials: SE
authors.lastname: Huskey
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics .
authors.forename: James B
authors.initials: JB
authors.lastname: Mangold
mesh_terms: D000328:Adult; D000613:Aminobutyrates / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000378:metabolism*; D000068756:Valsartan / Q000378:metabolism*
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Human ADME; LCZ696; and LBQ657; sabubitril; sacubitril/valsartan; valsartan