Effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation catalyzed by human liver microsomes and recombinant CYP2C9 variants (CYP2C9.1 and CYP2C9.3)

Shiozawa, Ayaka; Yamaori, Satoshi; Kamijo, Shinobu; Ohmori, Shigeru

doi:10.1016/j.dmpk.2020.10.003

Cited by 4 publications

(3 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of chitosan, PVA, and surfactant Tween 80 in the nanoformulation is responsible for the increased dissolution of simvastatin and influx against P-gp activity. The previous in vitro studies showed that the lactone ring in formulation F40 showed maximum stability in gastric pH, and no degradation of the lactone in 24 h was observed [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

A Study on Pharmacokinetic Functionalities and Safety Margins of an Optimized Simvastatin Nanoformulation

et al. 2023

View full text Add to dashboard Cite

A pharmaceutical formulation with favorable pharmacokinetic parameters is more likely to be efficacious and safe to overcome the failures of the drug resulting from lack of efficacy, poor bioavailability, and toxicity. In this view, we aimed to evaluate the pharmacokinetic functionalities and safety margin of an optimized CS-SS nanoformulation (F40) by in vitro/in vivo methods. The everted sac technique was used to evaluate the improved absorption of a simvastatin formulation. In vitro protein binding in bovine serum and mice plasma was performed. The formulation’s liver and intestinal CYP3A4 activity and metabolic pathways were investigated by the qRT-PCR technique. The excretion of cholesterol and bile acids was measured to demonstrate the formulation’s cholesterol depletion effect. Safety margins were determined by histopathology as well as fiber typing studies. In vitro protein binding results revealed the existence of a high percentage of free drugs (22.31 ± 3.1%, 18.20 ± 1.9%, and 16.9 ± 2.2%, respectively) compared to the standard formulation. The controlled metabolism in the liver was demonstrated from CYP3A4 activity. The formulation showed enhanced PK parameters in rabbits such as a lower Cmax, clearance, and a higher Tmax, AUC, Vd, and t1/2. qRT-PCR screening further proved the different metabolic pathways followed by simvastatin (SREBP-2) and chitosan (PPAR-γ pathway) in the formulation. The results from qRT-PCR and histopathology confirmed the toxicity level. Hence, this pharmacokinetic profile of the nanoformulation proved it has a unique synergistic hypolipidemic modality.

show abstract

Section: Discussionmentioning

confidence: 99%

A Study on Pharmacokinetic Functionalities and Safety Margins of an Optimized Simvastatin Nanoformulation

et al. 2023

View full text Add to dashboard Cite

show abstract

“…While this suggests that statins will be predominantly found in the less inhibitory acid form, the metabolism of statins is complex, involving acid/lactone interconversion by various pathways, including glucuronidation and elimination ( 34 , 35 ). As a result, both chemical forms of these statins are detected in human plasma after administration ( 36 ). This evidence suggests that SERCA inhibition by the lactone form may be possible in certain situations, e.g.…”

Section: Discussionmentioning

confidence: 99%

A novel machine learning-based screening identifies statins as inhibitors of the calcium pump SERCA

Cruz-Cortés¹,

Velasco-Saavedra²,

Gortari³

et al. 2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Several studies suggested that statins may reduce cancer mortality and may demonstrate some protective effects through the use of chemotherapy and radiation-induced cardiovascular toxicity [6]. Today, the search for new substances derived from statins to support treatment and to create more diverse products is essential in research [7,8].…”

Section: Introductionmentioning

confidence: 99%

A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation

et al. 2021

View full text Add to dashboard Cite

Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in cholesterol biosynthesis. Statin therapy reduces morbidity and mortality in those who are at high risk of cardiovascular disease. Monacolin J is a statin compound, which is an intermediate in the lovastatin biosynthesis pathway, in the fungus Aspergillus terreus. It is also found in red yeast rice, which is made by culturing rice with the yeast Monascus purpureus. Monacolin J has a hydroxyl substituent at position C’-8 of monacolin L. Here, a new statin derivative from monacolin J was made through the catalysis of CYP102A1 from Bacillus megaterium. A set of CYP102A1 mutants of monacolin J hydroxylation with high catalytic activity was screened. The major hydroxylated product was C-6’a-hydroxymethyl monacolin J, whose structure was confirmed using LC–MS and NMR analysis. The C-6’a-hydroxymethyl monacolin J has never been reported before. It showed a greater ability to inhibit HMG-CoA reductase than the monacolin J substrate itself. Human liver microsomes and human CYP3A4 also showed the ability to catalyze monacolin J in producing the same product of the CYP102A1-catalyzed reaction. This result motivates a new strategy for the development of a lead for the enzymatic and chemical processes to develop statin drug candidates.

show abstract

Effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation catalyzed by human liver microsomes and recombinant CYP2C9 variants (CYP2C9.1 and CYP2C9.3)

Cited by 4 publications

References 30 publications

A Study on Pharmacokinetic Functionalities and Safety Margins of an Optimized Simvastatin Nanoformulation

A Study on Pharmacokinetic Functionalities and Safety Margins of an Optimized Simvastatin Nanoformulation

A novel machine learning-based screening identifies statins as inhibitors of the calcium pump SERCA

A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation

Contact Info

Product

Resources

About