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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacokinetics of the active metabolite of benazepril, benazeprilat, and inhibition of plasma angiotensin-converting enzyme activity after single and repeated administrations to dogs.

Plasma pharmacokinetic variables of benazeprilat, the active metabolite of the angiotensin-converting enzyme (ACE) inhibitor benazepril, were evaluated in healthy Beagles. Benazeprilat was administered IV at a dosage of 0.5 mg/kg of body weight (n = 9). The elimination of half-life of benazeprilat was 3.5 hours, although an additional terminal phase was observed in some dogs. Vehicle (gelatin capsules) or benazepril at dosages of 0.125, 0.25, 0.5, or 1.0 mg/kg was administered orally as a single administration, then once daily for 15 consecutive days (n = 5 or 6/group). Peak benazeprilat concentrations were rapidly attained by 2 hours. Benazeprilat concentrations accumulated moderately with repeated administration, with a peak concentration that was 23% higher and an area under the concentration-time curve that was 34% higher after the 15th dose of benazepril, compared with values after a single dose. The effective half-life for accumulation for all 4 dosages was 12 hours. Steady-state concentrations at 2 hours after administration were achieved after a median (range) of 1 (1 to 6) dose(s). Pharmacodynamic variables were assessed by measurements of plasma ACE activity after oral administration of benazepril or vehicle. All dosages of benazepril caused profound inhibition of ACE, with rapid onset of activity (time to peak effect, 2 hours) and long duration of action (single administration of all 4 doses induced inhibition of ACE that was significantly different from the value in the control [vehicle-treated] dogs for all time points between 1 and 30 hours). Maximal inhibition at all time points was induced by the 0.25-mg/kg dosage at a single administration and with the lowest dosage tested (0.125 mg/kg) at steady state. At steady state, the 0.25-mg/kg dosage caused (mean +/- SEM) 96.9 +/- 2.0% inhibition of ACE activity at maximal effect and 83.6 +/- 4.2% at trough effect (24 hours after dosing), indicating minimal variation in peak/trough effect. Steady-state inhibition of ACE activity at both peak and trough drug effect was achieved after 1 to 4 doses. The data indicate that benazepril is a potent and long-acting ACE inhibitor in dogs.[1]


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