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Transport properties of valsartan, sacubitril, and its active metabolite (LBQ657) as determinants of disposition

Vapurcuyan, Arpine and Crouthamel, Matthew and Davis, John and Tran, Phi and Natrillo, Adrienne and Zhu, Bing (2017) Transport properties of valsartan, sacubitril, and its active metabolite (LBQ657) as determinants of disposition. Xenobiotica, omline (Publis). pp. 1366-5928. ISSN 0049-8254

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. The multi-drug resistance associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport which contributes to 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. The contribution of OATP1B3 to valsartan transport was appreciably higher than that by OATP1B1, suggesting that valsartan may be a useful probe substrate to examine consequences of the in vivo OATP1B3, but not OATP1B1, inhibition.
4. 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. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways and the low therapeutic concentration of the LCZ696 analytes.

Item Type: Article
Date Deposited: 16 Mar 2017 00:45
Last Modified: 16 Mar 2017 00:45
URI: https://oak.novartis.com/id/eprint/31888

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