Angiotensin-converting enzyme inhibitors metabolism

The effects of antihypertensive agents have been evaluated in patients taking ciclosporin. Collectively, dihydropyridine calcium channel blockers that do not affect ciclosporin blood concentrations substantially or at all (felodipine, isradipine, and nifedipine) are usually considered to be the drugs of choice. However, the risk of gingival hyperplasia with nifedipine, which ciclosporin also causes, should be borne in mind. Combination therapy with angiotensin-converting enzyme inhibitors or beta-blockers, or the use of other calcium channel blockers (verapamil or diltiazem) should also be considered, but careful monitoring of ciclosporin blood concentrations is recommended with the latter because they inhibit ciclosporin metabolism. 

Y Yamada, R Ohashi, Y Sugawara, M Otsuka, O Takaiti. Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. Arzneim Forsch/Drug Res 42 490, 1992. 

Angiotensin-converting enzyme inhibitors are effective in the treatment of hypertension and congestive heart failure. ACE inhibitors also prevent bra-dykinin metabolism and, as a result, may produce the side effect of cough and angioedema. Many of the known ACE inhibitors were developed without the aid of computational chemistry techniques. However, a number of studies have used computational methods to design mimics of other nonpeptidic ACE inhibitors. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

For compounds not metabolized by the gut wall, liver, or affected by transporters, a direct relationship between oral absorption and bioavailability should be observed. The calculated oral absorption, using PSA as a measure for passive membrane permeability reflecting the absorption step, relates to the in vivo observed bioavailability for three classes of compounds - angiotensin-converting enzymes (ACE) inhibitors, P-blockers, and calcium antagonists - is shown below [25],... 

L. Grislain, M. T. Mocquard, J. F. Dabe, M. Bertrand, W. Luijten, B. Marchand, G. Res-plandy, M. Devissaguet, Interspecies Comparison of the Metabolic Pathways of Perin-dopril, a New Angiotensin-Converting Enzyme (ACE) Inhibitor , Xenobiotica 1990, 20, 787 - 800. 

ACE inhibitors (ACEIs) (e.g., captopril) inhibit kininase II (angiotensin-converting enzyme), blocking the formation of angiotensin II and preventing its activation of AT-1 receptors in the adrenal cortex —> 4, aldosterone and its effect on vasculature, thereby i vasoconstriction. ACEIs also inhibit the metabolism of bradykinin (BK), which causes NO/EDRF-mediated vasodilation - l TPR. 

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