Key result
Oral administration of [14C] Sacubitril/Valsartan resulted in rapid metabolism to active LBQ657, with renal excretion accounting for 51.7-67.8% of total radioactivity.
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Sacubitril/valsartan is rapidly metabolized to its active neprilysin inhibitor LBQ657, which is primarily eliminated via renal excretion, with low potential for CYP-mediated drug interactions.
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.
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Flarakos et al. (2016) studied Healthy. [14C] Sacubitril/Valsartan was evaluated on Disposition, metabolism, and excretion routes. Oral administration of [14C] Sacubitril/Valsartan resulted in rapid metabolism to active LBQ657, with renal excretion accounting for 51.7-67.8% of total radioactivity.
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