Prodrugs enalapril

As a prodrug, enalapril is essentially inactive as an ACE inhibitor. Thus, it must be enzymatically converted to enalaprilat, and liver homogenates of rats, dogs, rhesus monkeys, and humans have that capacity (128). In humans and in all nonhuman species except the rhesus monkey, deesterification is the only metabolism which is observed. In monkeys, a small amount of the desproline metabolite of enalaprilat has been detected (128). Absorption of enalapril is reported to be 39% in rats, 64% in dogs, and 60-70% in humans (128). 

Molecules requiring activation (prodrugs) Enalaprilate, paracetamol... 

Enalapril, (S)-l-[N-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline, an orally active inhibitor of the angiotensinconverting enzyme (ACE). After oral administration, the prodrug enalapril (ICso = 1.2 X 10 M) is primarily bioactivated in the liver by hydrolysis of the ethyl ester to yield enalaprilat (IC50 =... 

Figure 9.16 Effective permeabilities and fraction absorbed for the ACE inhibitor enalaprilat and its prodrug, enalapril. (Reproduced with permission from Petri, N., Lennemas, H. In vivo Permeability Studies in the Gastrointestinal Tract of Humans , Chapter 7 in van de Waterbeemd, J., Lennerniis, H., Arturrson, P., Eds. Drug Bioavailability, WUey-VCH Verlag GmbH Co. KGaA, p. 171, copyright 2003).

With the exception of captopril and lisinopril, ACE inhibitors are not well absorbed orally and are administered as esters (prodrugs enalapril, cilazapril, etc.) which undergo hydrolysis in vivo to release the active drugs [110]. 

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. 

DI Friedman, GL Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats Enalapril and fosinopril. Pharm Res 6(12) 1043-1047, 1989. 

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... 

Quinapril (3, CI-906), marketed by Pfizer under the trade name Accupril , was discovered at Warner-Lambert (Klutchko et al., 1986). Like enalapril, quinapril is a prodrug, and is... 

Captopril and enalapril are the standard examples of ACE-inhibitors, which have been used on a large scale for almost two decades. The differences between the two preparations are predominantly based on pharmacokinetic parameters. Enalapril is a prodrug, which is converted into its active compound enalaprilate after oral ingestion captopril is active as such. Enalapril can be given once daily, whereas... 

Many of the orally active ACE inhibitors are prodrugs. These include perindopril, quinapril, benazepril, ramipril, enalapril, trandolapril, and fosinopril. 

While essentially all ACE inhibitors have a similar mechanism of action and therefore exhibit similar efficacy in the treatment of hypertension and congestive heart failure, these drugs differ slightly in their pharmacokinetic profiles. Enalapril, lisinopril, and quinapril are excreted primarily by the kidney, with minimal liver metabolism, while the other prodrug compounds are metabolized by the liver and renally excreted. Thus, in patients with renal insufficiency, the half-life of renally excreted ACE inhibitors is prolonged. In addition, patients with impaired liver func-... 

Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. 

For patients with severe liver disease, captopril and lisinopril (i.e. not prodrugs, and not requiring hepatic activation and having almost solely renal elimination) are recommended. Enalaprilat (Fig. 6.18), the active metabolite of enalapril, is the only available ACE-inhibitor which is given intravenously, and can be used in patients with severe liver dysfunction. 

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