Fosinopril: Pharmacokinetics and pharmacodynamics in congestive heart failure*

Abstract

Fosinoprilat, the active product of fosinopril, is eliminated by a hepatic pathway, in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors. Congestive heart failure (CHF) may elevate drug plasma concentrations caused by a reduction in steady-state volume of distribution (Vss) and/or an impairment of clearance. This study compared the pharmacokinetics and pharmacodynamics of fosinopril (intravenous and oral) in 10 patients with established CHF and 10 age-, sex-, and weight-matched normal control subjects. There were no statistically significant differences between the patients with CHF and the control patients with respect to maximum drug concentration (Cmax) or area under the plasma concentration-time curve from 0 to infinity. Absolute bioavailability was approximately 29%. Vss was similar, and protein binding was 99% in both groups. The oral half-life of fosinoprilat was significantly longer than the intravenous half-life for both the patients with CHF and normal subjects, without statistically significant differences between the study groups. Median time to reach Cmax occurred at 4 hours in each group and corresponded to maximum angiotensin converting enzyme inhibition, which was essentially complete through 12 hours and markedly reduced through 24 hours. Thus these data indicate that patients with CHF can receive fosinopril without undue increases in fosinoprilat concentrations. This probably is due to the dual excretory pathways.

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

“…Other indices of RAS activity have not been reported. These results were similar to those found for Caucasians, both normal 34 and with heart failure, and in single or steady-state dosing.…”

“…33 Fosinopril pharmacokinetics have been studied in 12 healthy Chinese and 10 healthy Caucasians using single 10.0 mg oral doses. 29,34 Data were combined from two studies which used the same methods and analytic techniques (one in Chinese 29 and one in Caucasians 34 ). Plasma concentrations across time (Table 1, rows 5 and 6 and Figure 1b) and renal clearance were similar in Chinese and Caucasians.…”

The influence of heart failure on the pharmacokinetics of cardiovascular and non‐cardiovascular drugs: a critical appraisal of the evidence

“…It is not possible to establish whether changes in liver and/or renal function might have influenced the results as the relevant information was not provided in this study . By contrast, no significant alterations in the pharmacokinetics of fosinopril and irbesartan were observed in HF .…”

“…A total of 59 studies (49 on cardiovascular drugs) investigating 36 drugs (31 cardiovascular) were identified (Tables ). Twelve studies were published in the period 1970–1979 , 20 in the period 1980–1989 , 12 in the period 1990–1999 , 10 in the period 2000–2009 , and five in the period 2010–2018 .…”

Synthesis of Benzothiophene‐Containing 10‐ and 11‐Membered Cyclic Phostones

“…In particular, phosphinate and phosphonate derivatives have been explored as transition‐state analogues and inhibitors of therapeutically relevant protease enzymes. Examples include the antihypertension drug fosinoprilat ( 1 , a potent inhibitor of the zinc‐metallopeptidase angiotensin‐converting enzyme; ACE) and preclinical anti‐inflammatory agent 2 (an inhibitor of the human mast cell chymase) . Six‐membered ring phosphinates (known as oxaphosphinanes or phostines) and phosphonates (known as phostones) have also been previously explored in drug discovery as bioisosteres of the furanose or pyranose ring, in which the anomeric carbon atom is replaced by the phosphinate or phosphonate moiety.…”