Quantitation of simvastatin and its ?-hydroxy acid in human plasma by liquid-liquid cartridge extraction and liquid chromatography/tandem mass spectrometry

Zhao, Jamie J.; Xie, Iris; Yang, Amy Y.; Roadcap, Brad

doi:10.1002/1096-9888(200009)35:9<1133::aid-jms42>3.0.co;2-x

Cited by 83 publications

(59 citation statements)

References 12 publications

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“…Plasma concentrations of simvastatin and its main active metabolite, simvastatin acid, were measured on Day 4 before the subject took the final dose of study drug, which was administered under supervision (1 h before LPS inhalation), as previously described (26). Additional assay details are provided in the online supplement.…”

Section: Assaysmentioning

confidence: 99%

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Shyamsundar¹,

McKeown²,

O'Kane³

et al. 2009

Am J Respir Crit Care Med

223

182

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Rationale: Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option. Objectives: To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers. Methods: Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n 5 10/group) for 4 days before inhalation of 50 mg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-kB (NF-kB) was measured in monocyte-derived macrophages. Measurements and Main Results: Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-a, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P , 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-kB in monocyte-derived macrophages (P , 0.001); pretreatment with simvastatin reduced this by 35% (P , 0.001). Conclusions: Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS. Clinical trial registered with www.controlled-trials.com (ISRCTN21056528).

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Section: Assaysmentioning

confidence: 99%

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Shyamsundar¹,

McKeown²,

O'Kane³

et al. 2009

Am J Respir Crit Care Med

223

182

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“…[13][14][15] Briefly, 300 mL 100 mM ammonium acetate, pH 4.5, with acetic acid glacial was added to each 500 mL sample of plasma. Each plasma sample was spiked with 50 mL of internal standard simvastatin in 100% acetonitrile.…”

Section: Lovastatin Plasma Measurementsmentioning

confidence: 99%

Locally delivered lovastatin nanoparticles enhance fracture healing in rats

Garrett

Gutiérrez

Rossini

et al. 2007

Journal Orthopaedic Research

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Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolonged infusions, stimulate biomechanical strength of murine long bones with healing fractures. However, administration of statins by large oral doses or prolonged infusions to a fracture site is not a feasible therapeutic approach to hasten healing of human fractures. We administered lovastatin in biodegradable polymer nanobeads of poly(lactic-co-glycolide acid) to determine if lovastatin delivered in low doses in nanoparticles of a therapeutically acceptable scaffold could increase rates of healing in a standard preclinical model of femoral fracture. We found that these nanobeads: (1) stimulated bone formation in vitro at 5 ng/mL, (2) increased rates of healing in femoral fractures when administered as a single injection into the fracture site, and (3) decreased cortical fracture gap at 4 weeks as assessed by microcomputed tomography. These preclinical results suggest that lovastatin administered in a nanobead preparation may be therapeutically useful in hastening repair of human fractures. ß

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“…For plasma samples, quantitation of SV and SVA was accomplished using LC/MS/MS as described previously (Zhao et al, 2000). In brief, SV and SVA were extracted at 4°C from dog plasma using Chem Elut cartridges (Varian, Palo Alto, CA), chromatographed using a Kromasil C 18 column (2 ϫ 50 mm, 4 m; Keystone Scientific, Bellefonte, PA) with a mobile phase of acetonitrile/ammonium acetate (75:25, 1 mM, pH 4.2), and detected by turbo ionspray on a PE Sciex (Ontario, Canada) API 365 tandem mass spectrometry with within-run polarity switching between negative ion (for SVA) and positive ion (for SV) monitoring.…”

mentioning

confidence: 99%

Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

Prueksaritanont¹,

Zhao²,

Ma³

et al. 2002

J Pharmacol Exp Ther

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267

181

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A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (ϳ4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [14 C]SVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8-and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.

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Quantitation of simvastatin and its ?-hydroxy acid in human plasma by liquid-liquid cartridge extraction and liquid chromatography/tandem mass spectrometry

Cited by 83 publications

References 12 publications

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Locally delivered lovastatin nanoparticles enhance fracture healing in rats

Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

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