Trandolapril
From Proteopedia
(Difference between revisions)
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* 2006 Sales: $50 Million | * 2006 Sales: $50 Million | ||
* Importance: Appears to have been an unsuccessful launch of a new [[Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available. | * Importance: Appears to have been an unsuccessful launch of a new [[Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available. | ||
| - | * | + | * 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> Trandolapril is rapidly metabolized into its highly active metabolite Trandolaprilat by hepatic enzymes. Trandolaprilat binds to the active site of <scene name='Trandolapril/Ace/1'>Angiotensin-Converting Enzyme</scene>, preventing ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Trandolapril/Bound/3'>binds Trandolaprilat</scene> using residues Tyr 496, Glu 368, Glu 395, Ser 339, Ala 338, His 367, His 371, Val 502, His 497, Lys 495, Tyr 504, Gln 265, Asp 399, Phe 441, Phe 511 and a Zinc Ion 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> Trandolapril is rapidly metabolized into its highly active metabolite Trandolaprilat by hepatic enzymes. Trandolaprilat binds to the active site of <scene name='Trandolapril/Ace/1'>Angiotensin-Converting Enzyme</scene>, preventing ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Trandolapril/Bound/3'>binds Trandolaprilat</scene> using residues Tyr 496, Glu 368, Glu 395, Ser 339, Ala 338, His 367, His 371, Val 502, His 497, Lys 495, Tyr 504, Gln 265, Asp 399, Phe 441, Phe 511 and a Zinc Ion to tightly affix the inhibitor to the active site of ACE-1. | ||
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{| 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 | ||
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! [[Trandolapril]] | ! [[Trandolapril]] | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr) |
! .98 | ! .98 | ||
! 6.5 | ! 6.5 | ||
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! .72 | ! .72 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml) |
! 1210 | ! 1210 | ||
! 79 | ! 79 | ||
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! 1.68 | ! 1.68 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%) |
! 72 | ! 72 | ||
! 25 | ! 25 | ||
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! 10 | ! 10 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Protein_Binding|Protein Binding]] (%) |
! 97 | ! 97 | ||
! 0 | ! 0 | ||
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! 80 | ! 80 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr) |
! .56 | ! .56 | ||
! 10.1 | ! 10.1 | ||
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! .68 | ! .68 | ||
|- | |- | ||
| - | ! [[ | + | ! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr) |
! 1673 | ! 1673 | ||
! 1016 | ! 1016 | ||
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! 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 11:21, 9 December 2010
|
Better Known as: Mavik
- Marketed By: Abbott Labs
- Major Indication: Hypertension & Congestive Heart Failure
- Drug Class: ACE Inhibitor
- Date of FDA Approval (Patent Expiration): 1996 (2006)
- 2006 Sales: $50 Million
- Importance: Appears to have been an unsuccessful launch of a new Angiotensin-Converting Enzyme Inhibitor in a market with several established compounds already available.
- 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] Trandolapril is rapidly metabolized into its highly active metabolite Trandolaprilat by hepatic enzymes. Trandolaprilat binds to the active site of , preventing ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 using residues Tyr 496, Glu 368, Glu 395, Ser 339, Ala 338, His 367, His 371, Val 502, His 497, Lys 495, Tyr 504, Gln 265, Asp 399, Phe 441, Phe 511 and a Zinc Ion 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
