Interconversion Pharmacokinetics of Simvastatin and its Hydroxy Acid in Dogs: Effects of Gemfibrozil
Abstract
Purpose To characterize the pharmacokinetics of simvastatin (SV) and simvastatin acid (SVA), a lactone-acid pair known to undergo reversible metabolism, and to better understand mechanisms underlying pharmacokinetic interactions observed between SV and gemfibrozil. Methods Pharmacokinetic studies were conducted after intravenous administration of SV and SVA to dogs pretreated with a vehicle or gemfibrozil. In vitro metabolism of SVA in dog hepatocytes as well as in vitro hepatic and plasma conversion of SV/SVA were investigated in the absence and presence of gemfibrozil. Results In control animals, the irreversible elimination clearances of SV (CL10) and SVA (CL20) were 10.5 and 18.6 ml min(-1) kg(-1), respectively. The formation clearance of SVA from SV (CL12 = 4.8 ml min(-1) kg(-1)) was 8-fold greater than that of SV from SVA (CL21 = 0.6 ml min(-1) kg(-1)), and the recycled fraction was relatively minor (0.009). In gemfibrozil-treated animals, CL10 was essentially unchanged, whereas CL12, CL20, CL21, and recycled fraction were significantly decreased to 2.9, 9, 0.14 ml min(-1) kg(-1), and 0.003, respectively. In control dogs, values for real volume of distribution at steady state (Vss,real) of SV (2.3 L kg(-1)) were much larger than the corresponding values of SVA (0.3 L kg(-1)). Gemfibrozil treatment did not affect Vss,real of either SV or SVA. In dog hepatocytes, gemfibrozil modestly affected the formation of CYP3A-mediated oxidative metabolites (IC50 > 200 microM) and beta-oxidative products (IC5) approximately 100 microM), but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of an SVA beta-oxidation product (IC50 = 18 microM). In in vitro dog and human liver S9 and plasma, hydrolysis of SV to SVA was much faster than that of SVA to SV. Gemfibrozil (250 microM) had a minimal inhibitory effect on the hydrolysis of either SV to SVA or SVA to SV in dog and human liver S9, but had a significant ( approximately 60%) inhibitory effect on the SV to SVA hydrolysis in both dog and human plasma. Conclusions In dogs, the interconversion process favored the formation of SVA and was less efficient than the irreversible elimination processes of SV and SVA. Treatment with gemfibrozil did not affect the distribution of SV/SVA, but rather affected the elimination of SVA and the SV/SVA interconversion processes. Gemfibrozil decreased CL20 and CL21 likely via its inhibitory effect on the glucuronidation of SVA, and not on the CYP3A-mediated oxidative metabolism of SV or SVA, the beta-oxidation of SVA, nor the SVA to SV hydrolysis. The decrease in CL12 might be due in part to the inhibitory effect of gemfibrozil on SV to SVA hydrolysis in plasma. Similar rationales may also be applicable to studies in humans and/or other statin lactone-acid pairs.
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Simvastatin is a hypolipidemic agent administered as an inactive prodrug, simvastatin lactone (SVL), which is converted to the active form, simvastatin acid (SVA), via carboxylesterases and paraoxonases mainly expressed in the liver and plasma.
“Simvastatin is a hypolipidemic agent administered as an inactive prodrug, simvastatin lactone (SVL), which is converted to the active form, simvastatin acid (SVA), via carboxylesterases and paraoxonases mainly expressed in the liver and plasma. 18 , 19 , 20”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [19]
The re-conversion of SVA to SVL is mainly mediated by paraoxonases and UGT1A1.
“The re‐conversion of this process (SVA‐to‐SVL) is mainly mediated by paraoxonases and UGT1A1. 19 , 21”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [19]
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- Authors
- Prueksaritanont, T., Qiu, Y., Mu, L., Michel, K., Brunner, J., Richards, K. M., & Lin, J. H.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Prueksaritanont, Thomayant
- Venue
- Pharmaceutical Research
- Published
- 2005-07
- Volume
- 22
- Issue
- 7
- Pages
- 1101-1109
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W2118023006
- Cited by
- 35
- References
- 36
- Citations by year
- 2025: 2 · 2024: 2 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 6 · 2013: 4
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- simvastatin, simvastatin acid, gemfibrozil, pharmacokinetic interactions, drug-drug interactions, glucuronidation, lactonization, CYP3A, fatty acid beta-oxidation, hepatic metabolism, dogs, elimination clearance, volume of distribution, hepatocytes, S9 fraction, plasma proteins
- MeSH terms
- Animals, Anticholesteremic Agents, Hypolipidemic Agents, Cells, Cultured, Dogs, Humans, Hydrolysis, Infusions, Intravenous, Liver, Gemfibrozil, Simvastatin, Hepatocytes
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