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Fosinopril: pharmacokinetics and pharmacodynamics in congestive heart failure
J B Kostis1, W T Garland, C Delaney
1University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick 08903, USA.
Insights
Patients with congestive heart failure (CHF) can safely take fosinopril. Pharmacokinetics and pharmacodynamics showed no significant differences in drug concentrations, likely due to dual elimination pathways.
Area of Science:
- Pharmacology
- Clinical Therapeutics
Background:
- Fosinoprilat, the active metabolite of fosinopril, undergoes both renal and hepatic elimination.
- Congestive heart failure (CHF) can alter drug pharmacokinetics, potentially increasing plasma concentrations due to reduced volume of distribution or impaired clearance.
Purpose of the Study:
- To compare the pharmacokinetics and pharmacodynamics of fosinopril in patients with CHF versus healthy controls.
- To assess the safety and efficacy of fosinopril in CHF patients.
Main Methods:
- A pharmacokinetic and pharmacodynamic study comparing intravenous and oral fosinopril in 10 CHF patients and 10 matched healthy controls.
- Measurements included maximum drug concentration (Cmax), area under the plasma concentration-time curve, absolute bioavailability, volume of distribution (Vss), protein binding, and half-life.
Main Results:
- No statistically significant differences in Cmax or area under the curve were observed between CHF patients and controls.
- Absolute bioavailability was approximately 29%, Vss was similar, and protein binding was 99% in both groups.
- Oral half-life of fosinoprilat was longer than intravenous half-life in both groups, without significant intergroup differences.
Conclusions:
- Patients with CHF can be treated with fosinopril without concerns of excessive drug accumulation.
- The dual hepatic and renal elimination pathways of fosinoprilat likely contribute to its predictable pharmacokinetic profile in CHF.
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.