Fluvastatin

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<applet load="" size="480" color="" frame="true" spin="on" Scene ="Fluvastatin/Fluvastatin/2" align="right" caption="Fluvastatin, also known as Lescol"/>
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<applet load="" size="[450,380]" color="" frame="true" spin="on" Scene ="Fluvastatin/Fluvastatin/2" align="right" caption="Fluvastatin, also known as Lescol"/>
===Better Known as: Lescol===
===Better Known as: Lescol===
* Marketed By: Novartis <br />
* Marketed By: Novartis <br />
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===Mechanism of Action===
===Mechanism of Action===
Fluvastatin is an inhibitor of [[HMG-CoA Reductase]] (HMGR), a highly <scene name='Fluvastatin/Hmg/1'>regulated enzyme</scene> responsible for the committed step in cholesterol synthesis.<ref>PMID:7784310</ref> Fluvastatin, like most of the statins, <scene name='Fluvastatin/Statin_fluva/1'>binds HMGR</scene> via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Fluvastatin contribute to binding as well.<ref>PMID:11349148</ref> These interactions help Fluvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.<ref>PMID:7784310</ref>
Fluvastatin is an inhibitor of [[HMG-CoA Reductase]] (HMGR), a highly <scene name='Fluvastatin/Hmg/1'>regulated enzyme</scene> responsible for the committed step in cholesterol synthesis.<ref>PMID:7784310</ref> Fluvastatin, like most of the statins, <scene name='Fluvastatin/Statin_fluva/1'>binds HMGR</scene> via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Fluvastatin contribute to binding as well.<ref>PMID:11349148</ref> These interactions help Fluvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.<ref>PMID:7784310</ref>
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===Pharmacokinetics===
===Pharmacokinetics===
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{| class="wikitable" border="1" width="48%" style="text-align:center"
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<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">
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|-
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<tr>
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! colspan="7" align="center"| Statin [[Pharmacokinetics]] at 10mg Dosage.<ref>PMID:11907637</ref><ref>PMID:15198967</ref><ref>PMID:12686673</ref><ref>PMID:18176327</ref><ref>PMID: 17452418</ref><ref>PMID:12895195</ref>
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<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
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|-
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<div style="height:100%; width: 100%">
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! Parameter
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{{:Statin Pharmacokinetics}}
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! [[Atorvastatin]] (Lipitor)
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</div>
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! [[Fluvastatin]] (Lescol)
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</td>
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! [[Lovastatin]] (Mevacor)
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</tr>
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! [[Simvastatin]] (Zocor)
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</table>
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! [[Rosuvastatin]] (Crestor)
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! [[Cerivastatin]] (Baycol)
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|-
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! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr)
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! 2.5
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! 1
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! 3
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! 1.5
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! 4
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! 1.5
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|-
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! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml)
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! 27-66
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! 448
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! 10-20
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! 7.3
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! 4.34
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! 3.43
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|-
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! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%)
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! 12
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! 19-29
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! 5
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! 5
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! 20
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! 60
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|-
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! [[Pharmacokinetics#Protein_Binding|Protein Binding]] (%)
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! 80-90
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! 99
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! 95
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! 95
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! 88
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! 99
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|-
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! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
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! 15-30
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! 2
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! 3
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! 2.7
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! 19
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! 2.2
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|-
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! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
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! 104
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! ~150
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! 33
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! 125
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! 48
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! 14.5
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|-
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! [[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
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! 154
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! 198
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! 800-4200
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! 66
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! 320
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! 50-90
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|-
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! Equivalent LDL Reduction Dosage (mg)
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! 10
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! --
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! 80
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! 20
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! 5
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! --
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|-
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! Metabolism
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! Hepatic <br/>(CYP3A4)
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! Hepatic <br/>(CYP2C9)
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! Hepatic <br/>(CYP3A4)
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! Hepatic <br/>(CYP3A4)
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! Not <br/>Metabolized
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! Hepatic <br />(CYP2C8)
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|}
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===References===
===References===

Revision as of 08:58, 10 December 2010

Fluvastatin, also known as Lescol

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Better Known as: Lescol

  • Marketed By: Novartis
  • Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
  • Drug Class: HMGR Inhibitor or Statin
  • Date of FDA Approval (Patent Expiration): 1993 (2011)
  • 2000 Sales: $430 Million
  • Importance: Was largely replaced by Lipitor. Statins are so ubiquitous, doctors have even suggested handing them out with fast food. See: the article
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Fluvastatin is an inhibitor of HMG-CoA Reductase (HMGR), a highly responsible for the committed step in cholesterol synthesis.[1] Fluvastatin, like most of the statins, via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Fluvastatin contribute to binding as well.[2] These interactions help Fluvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.[3]

Pharmacokinetics

Statin Pharmacokinetics at 10mg Dosage
Parameter Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Simvastatin (Zocor) Rosuvastatin (Crestor) Cerivastatin (Baycol)
Tmax (hr) 2.5 1 3 1.5 4 1.5
Cmax (ng/ml) 27-66 448 10-20 7.3 4.34 3.43
Bioavailability (%) 12 19-29 5 5 20 60
Protein Binding (%) 80-90 99 95 95 88 99
T1/2 (hr) 15-30 2 3 2.7 19 2.2
AUC (ng/ml/hr) 104 ~150 33 125 48 14.5
IC50 (nM) 154 198 800 66 320 50-90
Equivalent LDL Reduction Dosage (mg) 10 -- 80 20 5 --
Metabolism Hepatic
(CYP3A4) 		Hepatic
(CYP2C9) 		Hepatic
(CYP3A4) 		Hepatic
(CYP3A4) 		None Hepatic
(CYP2C8)

For References, See References

References

  1. ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310
  2. ↑ Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001 May 11;292(5519):1160-4. PMID:11349148 doi:10.1126/science.1059344
  3. ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310


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David Canner, Alexander Berchansky

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