Enalaprilat

The structural relationship of pivopril to the commercially important analogues captopril (51) and enalaprilat (52) is readily apparent. 

Enalaprilat 4-6 hour Up to 30 minute 1.25-40 mg q6 hour Hyperkalemia, renal failure, cough, anaphylaxis Useful in left ventricular dysfunction, variable response, should not be given in pregnancy... 

Enalaprilat 1.25-5 mg every 6 hours 1 5-30 minutes 6-12 hours Precipitous fall in pressure in high-renin states variable response Acute left ventricular failure avoid in acute myocardial infarction... 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Lennernas, H., Ahrenstedt, O., Ungell, A. L., Intestinal drug absorption during induced net water absorption in man a mechanistic study using antipyrine, atenolol and enalaprilat, Br. J. Clin. Pharmacol. 

Swaan, P. W., Stenhouwer, M. C., Tukker, J., Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors enalapril, enalaprilat, and lisinopril, Biochim. Biophys. Acta 1995, 3236, 31-38. 

Lennernas H, Ahrenstedt O and Ungell AL (1994) Intestinal Drug Absorption During Induced Net Water Absorption in Man a Mechanistic Study Using Antipyrine, Atenolol and Enalaprilat. Br J Clin Pharmacol 37 pp 589-596. 

Figure 7.3 Correlation analysis for Fapp values across freshiy isolated animal buccal mucosa and freshly isolated human buccal mucosa of Lucifer yellow, enalaprilat, atenolol, caffeine, sumatriptan, and fentanyl. Results from internal study by Absorption Systems Company.

P. W. Swaan, M. C. Stehouwer, J. J. Tukker, Molecular Mechanism for the Relative Binding Affinity to the Intestinal Peptide Carrier. Comparison of Three ACE-Inhibitors Enalapril, Enalaprilat and Lisinopril , Biochim. Biophys. Acta 1995, 1236, 31-38. 

Let me emphasize the magnitude of the problem with a simple example. I was once asked to estimate the number of compounds covered by a typical issued patent for a drug of commercial interest. The patent that I selected to analyze was for enalapril, a prominent prodrug ACE inhibitor with a well-established commercial market. Given the parameters as outlined in the patent covering enalapril, an estimation of the total number of compounds included in the generic claim for enalaprilat, the active... 

ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy the enzyme as false substrates. Affinity significantly influences efficacy and rate of elimination. 

Enalaprilat has a stronger and longer-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

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