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Cited by 29Pharmacogenetics and Drug MetabolismAnalytical Methods in PharmaceuticalsParaoxonase enzyme and polymorphisms

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Role of esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on pharmacokinetic profiles of simvastatin and its active metabolite in rat

Li, Ziwei, Zhang, Jun, Zhang, Yufeng, Zuo, Zhong·2019·Journal of Pharmaceutical and Biomedical Analysis
DOI 10.1016/j.jpba.2019.02.004
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Abstract

Simvastatin is known as a pro-drug, which could be hydrolyzed by esterases to its active form, simvastatin acid. Although pharmacokinetics of simvastatin and simvastatin acid have been widely studied, hydrolysis of simvastatin to simvastatin acid during blood sampling and plasma preparation has been overlooked in the previous studies, leading to underestimation of simvastatin concentration and overestimation of simvastatin acid concentration in plasma. Since both efficacy and adverse drug reaction of simvastatin are highly dependent on simvastatin and simvastatin acid concentrations in vivo, accurate assessment of the two compounds are critical in their pharmacokinetic and pharmacodynamic studies. The current study was proposed aiming to investigate the esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on the pharmacokinetic study of simvastatin and simvastatin acid. Using various esterase inhibitors including potassium florid (KF), bis(4-nitrophenyl) phosphate (BNPP), and ethylenediaminetetraacetic acid (EDTA), carboxylesterase was found to be the major esterase that hydrolyzed simvastatin in rat blood, while carboxylesterase and paraoxonase were the major esterases mediating the hydrolysis of simvastatin in human blood. Further studies using human recombinant enzymes identified simvastatin as substrates of PON1, CES1b, PON3 and CES1c with Cl int of 8.75, 5.77, 3.93, and 2.45 μL/min/mg protein. Therefore, inhibition treatments with 20 mM BNPP and 50 mM KF/ 10 mM EDTA were developed to efficiently prevent the hydrolysis of simvastatin during blood sampling and plasma preparation in rat/human. The subsequent pharmacokinetics of orally administered simvastatin at 8.66 mg/kg in rats found that the C max and AUC 0-∞ of simvastatin in absence of such esterase inhibitors in the blood sampling process were only 17.04 ± 6.60% and 15.30 ± 6.76% of those in presence of the inhibitors, whereas the C max and AUC 0-∞ of simvastatin acid were 1.60 ± 0.30 and 1.80 ± 0.22 times of that obtained in presence of the inhibitors. Nevertheless, T 1/2 of simvastatin and simvastatin acid remained the same regardless of the blood sampling method. Our current study for the first time demonstrated the importance for assessment of simvastatin stability during the blood sampling and plasma preparation process, which may be applicable to therapeutic drug monitoring of not only simvastatin but also other pro-drugs/compounds sharing similar metabolic properties.

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Metadata

Authors
Li, Z., Zhang, J., Zhang, Y., & Zuo, Z.
Affiliations
Chinese University of Hong Kong (HK)
Corresponding author
Zuo, Zhong
ORCID
Venue
Journal of Pharmaceutical and Biomedical Analysis
Publisher
Elsevier BV
Published
2019-05
Volume
168
Pages
13-22
ISSN
0731-7085 (ISSN-L)
DOI
10.1016/j.jpba.2019.02.004
OpenAlex
W2912272555
Cited by
29
References
1
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 1 · 2022: 9 · 2021: 2 · 2020: 3
FWCI
3.55
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Pharmaceutical and Biomedical Analysis (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords
simvastatin acid, prodrug activation, carboxylesterase, paraoxonase, esterase inhibitors, plasma preparation, pharmacokinetics, statins, HMG-CoA reductase inhibition
MeSH terms
Administration, Oral, Animals, Enzyme Inhibitors, Esterases, Humans, Hydrolysis, Male, Prodrugs, Species Specificity, Drug Monitoring, Rats, Sprague-Dawley, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Area Under Curve, Simvastatin, Rats

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