ChemInform Abstract: HMG‐CoA Reductase Inhibitors: An Exciting Development in the Treatment of Hyperlipoproteinemia

Kathawala, F. G.

doi:10.1002/chin.199126316

Cited by 5 publications

(10 citation statements)

References 1 publication

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“…The site of action of statins is within the hepatocytes, and fluvastatin efficacy is therefore related to the hepatocyte exposure to 3R,5S‐fluvastatin . The maximum fluvastatin dose (80 mg/day) reduces Low‐density lipoprotein cholesterol on average by 33%, which is less than that seen with the maximum doses of rosuvastatin and atorvastatin.…”

Section: Discussionmentioning

confidence: 99%

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Enantiospecific Pharmacogenomics of Fluvastatin

Hirvensalo

Tornio

Neuvonen

et al. 2019

Clin Pharma and Therapeutics

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The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration‐time curve (AUC) of both 3R,5S‐fluvastatin and 3S,5R‐fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10−9 and P = 3.19 × 10−12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S‐fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10−8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single‐nucleotide variations may affect the AUC of 3S,5R‐fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.

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Section: Discussionmentioning

confidence: 99%

“…Fluvastatin is a 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitor, which is used in the treatment of hypercholesterolemia. It is a racemic mixture of two enantiomers, of which 3R,5S‐fluvastatin is 30 times more active than 3S,5R‐fluvastatin . Fluvastatin is extensively metabolized via cytochrome P450 (CYP) 2C9 .…”

mentioning

confidence: 99%

Enantiospecific Pharmacogenomics of Fluvastatin

Hirvensalo

Tornio

Neuvonen

et al. 2019

Clin Pharma and Therapeutics

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“…However, the therapeutic activity is 30-fold higher for the (+)-3R, 5S-FV than (-)-3S, 5R-FV enantiomer ( Fig. 1) (Kathawala, 1991;Kirchheiner et al, 2003).…”

Section: Introductionmentioning

confidence: 93%

“…Fluvastatin (FV) is reversible, competitive and highly specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase used in the hypercholesterolemia treatment (Kathawala, 1991;Davignon et al, 1992;Al-Rawithi et al, 2003;Lachote et al, 2001;Um et al, 2006;Di Pietro et al, 2006). Moderate reduction in serum cholesterol levels by about 20-30% is achieved with daily doses of 20-40 mg. FV is marketed as a racemic mixture of the (+)-3R,5S and (-)-3S, 5R enantiomers.…”

Section: Introductionmentioning

confidence: 97%

Chiral separation of fluvastatin enantiomers by capillary electrophoresis

et al. 2008

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An analytical CE method was developed for the enantiomeric purity determination of fluvastatin enantiomers. Fluvastatin enantiomers were separated on an uncoated fused silica with 100 mM-borate solution containing 30 mg/mL of (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD) as running buffer and fenoprofen as an internal standard. The linearity was observed within a 400-700 microg/mL concentration range (r(2)>or=0.995) for both fluvastatin enantiomers. The repeatability expressed as coefficient of variation (CV) of the method were 0.96 and 0.92% for (+)-3R, 5S and (-)-3S, 5R-fluvastatin, respectively. The limit of detection and quantification for both fluvastatin enantiomers were 1.5 microg/mL and 2.5 microg/mL, respectively.

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“…In addition, the higher dose of statins and with other hypolipidemic agents like fibric acid derivatives may worsen the situation . Fluvastatin (FLU), (3R, 5S, 6E)‐7‐[3‐(4‐fluorophenyl)‐1‐(propan‐2‐yl)‐1H–indol‐2‐yl]‐3, 5‐dihydroxyhept‐6‐enoic acid, an 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitor, synthetic drug from the class of statins, used to treat hypercholesterolemia and cardiovascular diseases …”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of fluvastatin metabolites in rats by UHPLC/Q‐TOF/MS/MS and in silico toxicological screening of the metabolites

Chavan¹,

Kalariya²,

Nimbalkar

et al. 2017

J. Mass Spectrom.

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The present study reports the in vivo and in vitro identification and characterization of metabolites of fluvastatin, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, using liquid chromatography-mass spectrometry (LC-MS). In vitro studies were conducted by incubating the drug with human liver microsomes and rat liver microsomes. In vivo studies were carried out by administration of the drug in the form of suspension to the Sprague-Dawley rats followed by collection of urine, faeces and blood at different time points up to 24 h. Further, samples were prepared by optimized sample preparation method, which includes freeze liquid extraction, protein precipitation and solid phase extraction. The extracted and concentrated samples were analysed using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. A total of 15 metabolites were observed in urine, which includes hydroxyl, sulphated, desisopropyl, dehydrogenated, dehydroxylated and glucuronide metabolites. A few of the metabolites were also present in faeces and plasma samples. In in vitro studies, a few metabolites were observed that were also present in in vivo samples. All the metabolites were characterized using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry in combination with accurate mass measurement. Finally, in silico toxicity studies indicated that some of the metabolites show or possess carcinogenicity and skin sensitization. Several metabolites that were identified in rats are proposed to have toxicological significance on the basis of in silico evaluation. However, these metabolites are of no human relevance. Copyright © 2017 John Wiley & Sons, Ltd.

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ChemInform Abstract: HMG‐CoA Reductase Inhibitors: An Exciting Development in the Treatment of Hyperlipoproteinemia

Cited by 5 publications

References 1 publication

Enantiospecific Pharmacogenomics of Fluvastatin

Enantiospecific Pharmacogenomics of Fluvastatin

Chiral separation of fluvastatin enantiomers by capillary electrophoresis

Identification and characterization of fluvastatin metabolites in rats by UHPLC/Q‐TOF/MS/MS and in silico toxicological screening of the metabolites

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