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.

Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

“…Because of the polypharmacy situation in the clinical therapy of NASH patients who are prescribed drugs to manage other co-morbid conditions, it becomes relevant to understand the pros and cons of the various co-medications with respect to disposition from both CYP enzymes and hepatic/renal transporters. Few examples are presented: a) Drugs that are similar to fasiglam (TAK-875) that inhibit MRP2/MRP3, OATP and NTCP (i.e., perpetrator drug) would need dose adjustment(s) during the clinical therapy of NASH patients (69); b) Drugs like bosentan which is metabolized by CYPs 3A4 and 2C9; and owing to its inhibition of uptake transporters and bile acid transporters, should be dosed with caution in NASH patients (70); c) The newly approved LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) may present as both a perpetrator/victim drug in NASH patients owing to the involvement of inhibition of uptake transporters and dependence on MRP2 for its excretion (64,71).…”

Lopinavir-Ritonavir in SARS-CoV-2 Infection and Drug-Drug Interactions with Cardioactive Medications

“…Ritonavir is an inhibitor of OATP1B1 in vitro but is unlikely to inhibit it in the dose used with lopinavir. Coadministration has not been studied but a clinically significant interaction is unlikely [93].…”

Preliminary Evaluation of Pullulan Nanoparticles Loaded with Valsartan

“…Valsartan is an angiotensin II receptor antagonist drug commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, mainly for patients who are unable to tolerate angiotensin-converting enzyme inhibitors. Several clinical trials revealed that valsartan improves cardiovascular diseases outcome including reducing risk of myocardial infarction, stroke and the progression of heart failure [10,11]. Valsartan has poor solublility in water (1.406 mg/L, 25 °C).…”