Perindopril
From Proteopedia
(Difference between revisions)
| Line 7: | Line 7: | ||
* 2005 Sales: $1 Billion | * 2005 Sales: $1 Billion | ||
* Importance: One of the best selling [[Angiotensin-Converting Enzyme]] Inhibitors of all time. | * Importance: One of the best selling [[Angiotensin-Converting Enzyme]] Inhibitors of all time. | ||
| - | * | + | * See [[Pharmaceutical Drugs]] for more information about other drugs and diseases. |
===Mechanism of Action=== | ===Mechanism of Action=== | ||
Angiotensin II has been implicated in cardiac, renal and vascular diseases. Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for [[Hypertension]].<ref>PMID:17083068</ref> Perindopril is rapidly metabolized into its highly active metabolite Perindoprilat by hepatic enzymes. Perindoprilat binds to the active site of <scene name='Perindopril/Perindoprilat_ace/1'>Angiotensin-Converting Enzyme</scene>, actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Perindopril/Perindoprilat_binding/1'>binds Perindoprilat</scene> using residues Gln 265, Lys 495, Tyr 504, His 497, His 337, Tyr 496, Ala 338, Glu 368, His 367, HIs 371, Glu 395 and Asp 399 to tightly affix the inhibitor to the active site of ACE-1. | Angiotensin II has been implicated in cardiac, renal and vascular diseases. Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for [[Hypertension]].<ref>PMID:17083068</ref> Perindopril is rapidly metabolized into its highly active metabolite Perindoprilat by hepatic enzymes. Perindoprilat binds to the active site of <scene name='Perindopril/Perindoprilat_ace/1'>Angiotensin-Converting Enzyme</scene>, actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Perindopril/Perindoprilat_binding/1'>binds Perindoprilat</scene> using residues Gln 265, Lys 495, Tyr 504, His 497, His 337, Tyr 496, Ala 338, Glu 368, His 367, HIs 371, Glu 395 and Asp 399 to tightly affix the inhibitor to the active site of ACE-1. | ||
| Line 14: | Line 14: | ||
{| class="wikitable" border="1" width="50%" style="text-align:center" | {| class="wikitable" border="1" width="50%" style="text-align:center" | ||
|- | |- | ||
| - | ! colspan="8" align="center"| ACE-Inhibitor [[ | + | ! colspan="8" align="center"| ACE-Inhibitor [[Pharmacokinetics]] Comparison at Equivalent Dosages <ref>PMID: 7867683</ref><ref>DOI: 10.1111/j.1365-2710.2005.00646.x</ref><ref>PMID: 16075412</ref><ref>PMID:7527101</ref> |
|- | |- | ||
! Parameter | ! Parameter | ||
| Line 25: | Line 25: | ||
! [[Trandolapril]] | ! [[Trandolapril]] | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr) |
! .98 | ! .98 | ||
! 6.5 | ! 6.5 | ||
| Line 34: | Line 34: | ||
! .72 | ! .72 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml) |
! 1210 | ! 1210 | ||
! 79 | ! 79 | ||
| Line 43: | Line 43: | ||
! 1.68 | ! 1.68 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%) |
! 72 | ! 72 | ||
! 25 | ! 25 | ||
| Line 52: | Line 52: | ||
! 10 | ! 10 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Protein_Binding|Protein Binding]] (%) |
! 97 | ! 97 | ||
! 0 | ! 0 | ||
| Line 61: | Line 61: | ||
! 80 | ! 80 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr) |
! .56 | ! .56 | ||
! 10.1 | ! 10.1 | ||
| Line 70: | Line 70: | ||
! .68 | ! .68 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr) |
! 1673 | ! 1673 | ||
! 1016 | ! 1016 | ||
| Line 79: | Line 79: | ||
! 1.86 | ! 1.86 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM) |
! 1.1 | ! 1.1 | ||
! 5.5 | ! 5.5 | ||
Revision as of 11:19, 9 December 2010
|
Better Known as: Aceon
- Marketed By: Abbott Labs & Servier
- Major Indication: Hypertension & Congestive Heart Failure
- Drug Class: ACE Inhibitor
- Date of FDA Approval (Patent Expiration): 1993 (2009)
- 2005 Sales: $1 Billion
- Importance: One of the best selling Angiotensin-Converting Enzyme Inhibitors of all time.
- See Pharmaceutical Drugs for more information about other drugs and diseases.
Mechanism of Action
Angiotensin II has been implicated in cardiac, renal and vascular diseases. Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for Hypertension.[1] Perindopril is rapidly metabolized into its highly active metabolite Perindoprilat by hepatic enzymes. Perindoprilat binds to the active site of , actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 using residues Gln 265, Lys 495, Tyr 504, His 497, His 337, Tyr 496, Ala 338, Glu 368, His 367, HIs 371, Glu 395 and Asp 399 to tightly affix the inhibitor to the active site of ACE-1.
Pharmacokinetics
| ACE-Inhibitor Pharmacokinetics Comparison at Equivalent Dosages [2][3][4][5] | |||||||
|---|---|---|---|---|---|---|---|
| Parameter | Captopril | Lisinopril | Ramipril | Enalapril | Benazepril | Perindopril | Trandolapril |
| Tmax (hr) | .98 | 6.5 | .67 | 1.06 | .5 | .75 | .72 |
| Cmax (ng/ml) | 1210 | 79 | 16.4 | 314 | 149 | 105 | 1.68 |
| Bioavailability (%) | 72 | 25 | 28 | 60 | 97 | 24 | 10 |
| Protein Binding (%) | 97 | 0 | 73 | 20 | 97 | 20 | 80 |
| T1/2 (hr) | .56 | 10.1 | 1.93 | 1.6 | 10 | .9 | .68 |
| AUC (ng/ml/hr) | 1673 | 1016 | 21.9 | 450 | 140 | 182 | 1.86 |
| IC50 (nM) | 1.1 | 5.5 | 5.0 | 5.4 | 1.7 | 2.4 | 2.5 |
| Dosage (mg) | 10 | 20 | 5 | 20 | 10 | 4 | 2 |
| Metabolism | Hepatic (CYP2D6) | None | Hepatic | Hepatic (CYP3A4) | Hepatic | Hepatic | Hepatic (CYP2D6 & CYP2C9) |
References
- ↑ Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006 Mar;7(1):3-14. PMID:17083068
- ↑ Sun JX, Cipriano A, Chan K, John VA. Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects. Eur J Clin Pharmacol. 1994;47(3):285-9. PMID:7867683
- ↑ Arafat T, Awad R, Hamad M, Azzam R, Al-Nasan A, Jehanli A, Matalka K. Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays. J Clin Pharm Ther. 2005 Aug;30(4):319-28. PMID:15985045 doi:10.1111/j.1365-2710.2005.00646.x
- ↑ Tamimi JJ, Salem II, Alam SM, Zaman Q, Dham R. Bioequivalence evaluation of two brands of lisinopril tablets (Lisotec and Zestril) in healthy human volunteers. Biopharm Drug Dispos. 2005 Nov;26(8):335-9. PMID:16075412 doi:10.1002/bdd.465
- ↑ Arner P, Wade A, Engfeldt P, Mouren M, Stepniewski JP, Sultan E, Bryce T, Lenfant B. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S44-9. PMID:7527101
