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| __NOTOC__
| | #REDIRECT [[Trandolapril#Pharmacology]] |
| {{Trandolapril}}
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| {{CMG}}; {{AE}} {{AM}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| Trandolapril is deesterified to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of [[angiotensin I]] to the vasoconstrictor, [[angiotensin II]]. [[Angiotensin II]] is a potent peripheral vasoconstrictor that also stimulates secretion of [[aldosterone]] by the [[adrenal cortex]] and provides negative feedback for renin secretion. The effect of trandolapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing [[angiotensin II]] formation, decreasing vasoconstriction, decreasing aldosterone secretion, and increasing plasma [[renin]]. Decreased aldosterone secretion leads to [[diuresis]], [[natriuresis]], and a small increase of serum potassium. In controlled clinical trials, treatment with MAVIK alone resulted in mean increases in potassium of 0.1 mEq/L.
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| ACE is identical to kininase II, an enzyme that degrades [[bradykinin]], a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of trandolapril remains to be elucidated.
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| While the principal mechanism of antihypertensive effect is thought to be through the [[renin-angiotensin-aldosterone system]], trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. MAVIK was an effective antihypertensive in all races studied. Both black patients (usually a predominantly low-renin group) and non-black patients responded to 2 to 4 mg of MAVIK.
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| ====Pharmacokinetics and Metabolism====
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| ====Pharmacokinetics====
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| Trandolapril's ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat. Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion. Absolute bioavailability after oral administration of trandolapril is about 10% as trandolapril and 70% as trandolaprilat. After oral trandolapril under fasting conditions, peak trandolapril levels occur at about one hour and peak trandolaprilat levels occur between 4 and 10 hours. The elimination half-life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing binding to plasma and tissue ACE. During multiple dosing of trandolapril, there is no significant accumulation of trandolaprilat. Food slows absorption of trandolapril, but does not affect AUC or Cmax of trandolaprilat or Cmax of trandolapril. | |
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| ====Metabolism and Excretion====
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| After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been determined. Plasma concentrations (Cmax and AUC of trandolapril and Cmax of trandolaprilat) are dose proportional over the 1-4 mg range, but the AUC of trandolaprilat is somewhat less than dose proportional. In addition to trandolaprilat, at least 7 other metabolites have been found, principally glucuronides or deesterification products.
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| Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.
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| The volume of distribution of trandolapril is about 18 liters. Total plasma clearances of trandolapril and trandolaprilat after approximately 2 mg IV doses are about 52 liters/hour and 7 liters/hour respectively. Renal clearance of trandolaprilat varies from 1-4 liters/hour, depending on dose.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = MAVIK (TRANDOLAPRIL) TABLET [ABBVIE INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ad67ea2-409c-4f52-a9b8-38216209609a | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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