title: Transport properties of valsartan, sacubitril and its active metabolite (LBQ657) as determinants of disposition.
abstract: 1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed. 4. The contribution of OATP1B3 to valsartan transport (73%) was appreciably higher than that by OATP1B1 (27%), Alternatively, OATP1B1 contribution to the hepatic uptake of LBQ657 (∼70%) was higher than that by OATP1B3 (∼30%). 5. None of the compounds inhibited OCT1/OCT2, MATE1/MATE2-K, P-gp, or BCRP. Sacubitril and LBQ657 inhibited OAT3 but not OAT1, and valsartan inhibited the activity of both OAT1 and OAT3. Sacubitril and valsartan inhibited OATP1B1 and OATP1B3, whereas LBQ657 weakly inhibited OATP1B1 but not OATP1B3. 6. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways (LBQ657: OATP1B1/OAT1/3 and valsartan: OATP1B3/OAT1/3) and the low therapeutic concentration of the LCZ696 analytes.
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Natalya
authors.initials: N
authors.lastname: Alexander
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Crouthamel
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Natrillo
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Phi
authors.initials: P
authors.lastname: Tran
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Arpine
authors.initials: A
authors.lastname: Vapurcuyan
authors.affiliation: a Novartis Institutes for BioMedical Research East Hanover, Drug Metabolism and Pharmacokinetics , East Hanover , NJ , United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000613:Aminobutyrates / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000493:pharmacokinetics*; D000068756:Valsartan / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000613:Aminobutyrates; D001713:Biphenyl Compounds; D002265:Carboxylic Ester Hydrolases; D004338:Drug Combinations; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D013777:Tetrazoles; D000068756:Valsartan; C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C000609743:LBQ657; C503999:SLCO1B1 protein, human; C474609:CES1 protein, human; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: BCRP; LBQ657; MATE; OAT; OATP; OCT; P-glycoprotein; drug transport; drug–drug interactions; sacubitril; valsartan