A Study Of Benazepril And Its Metabolite In Chinese Healthy Volunteers

A Study of Benazepril and Its Metabolite in Chinese Healthy Volunteersâ… .Objective:Benazepril and its active metabolite benazeprilat inhibit angiotensin-converting enzyme(ACE) and reduce the activity of ACE. But the activity of benazeprilat is 1000 times higher than that of benazepril. Studies about pharmacokinetics and pharmacodynamics of benazepril and benazeprilat have been done a lot abroad. But related data in Chinese is rare. In order to know more about the pharmacokinetics and pharmacodynamics of benazepril and its metabolite in Chinese,we design and carry out the clinical trial.â…¡Method1.Quantitative determination of benazepril and its metaboliteAfter fully validation, the plasma concentration of benazepril and its metabolite benazeprilat was determined simultaneously by liquid chromatography-tandem mass spectrometry (LC/MS/MS) established in our lab.2.Dosage regimen and collection of blood sample24 healthy male volunteers received a single oral dose of 20mg benazepril tablet .Plasma samples were collected at 0.25h,0.5h,0.75h,1h,1.5h,2h,3h,4h,6h,8h,12h,15h,24h after drug administration for the determination of plasma concentration of benazepril and benazeprilat.3.Indexes under observation 3.1 Blood pressure was measured at lying position immediately prior to and at 1h,2h,3h,4h,8h,12h,24h after the drug administration.3.2 Breath and heart rates were counted at lying position immediately prior to and at 1h,2h,3h,4h,8h,12h,24h after the drug administration.3.3 Physical examination was performed one day before and at 24h after the drug administration.3.4 Blood and urine routine test was performed one day before and at 24h after the drug administration .Stool routine test and blood chemistry test was performed at 24h after the drug administration.3.5 Electrocardiogram was performed immediately prior to and at 4h,12h,24h after the drug administration.3.6 Electrocardiogram monitoring was performed from one day before untill 24h after the drug administration.â…¢Result1. Assessment of pharmacokinetic properties of benazepril1.1 24 healthy male volunteers, age 19-37 years (average 27), weight 58-85kg (average 67.08 kg).1.2 Pharmacokinetics of benazepril:Time to peak plasma concentration (T_max) of benazepril was reached at 0.47±0.20h. Peak benazepril concentration (C_max) was 226.3±110.3 ng/ml. Area under plasma concentration-time curves from 0 to 8h (AUC₀₈) and from 0 to infinity after drug administration (AUC_0-∞) were 179.7±73.5 ng^*h/ml and 180.3±73.6ng^*h/ml, respectively. And plasma elimination half-life(t_1/2) was 1.30±0.16h.2. Assessment of pharmacokinetic properties of benazeprilatTime to peak plasma concentration (T_max) of benazeprilat was reached at 1.31±0.36h. Peak benazeprilat concentration (C_max)was 266.6±105.9 ng/ml. Area under plasma concentration-time curves from 0 to 24h (AUC_0-24) and from 0 to infinity (AUC_0-∞) were 1124.8±466.6 ng^*h/ml and 1155.3±481.8 ng^*h/ml, respectively. And plasma elimination half-life (t_1/2) was 5.41±0.80h.3. Contrast between benazepril and its active metaboliteThe most significant difference of plasma concentration betwteen benazepril and benazeprilat was observed at 1.5h after the drug administration. At that time, plasma concentration of benazeprilat is almost 6 times higher than that of benazepril. AUC and C_max of benazeprilat are much higher than those of benazepril evidently. A peak plasma concentration of benazeprilat was achieved later than that of benazepril (1.31h vs 0.47h, p＜0.05). And t_1/2 of the metabolite is remarkably longer than that of the parent drug (5.41h vs 1.30h, p＜0.05)。4. Pharmacodynamics4.1 Systolic/diastolic pressure decreased 3.20-8.54 mmHg/ 4.67-10.04mmHg after 24 healthy male volunteers received a single doses of 20mg benazepril tablet. The lowest systolic pressure was observed at 2h and the lowest diastolic pressure was observed at 4h after the drug administration. It showed that time to the lowest blood pressure was later than time to peak plasma concentrations for both of benazepril and benazeprilat.4.2 The correlation analysis between plasma concentrations of benazeprilat and decreasing deference of blood presure:4.2.1 plasma concentrations of benazepril versus decreasing deference of systolic pressure: R=0.039, R²=0.0014, P=0.673.4.2.2 plasma concentrations of benazepril versus decreasing deference of diastolic pressure: R=-0.235, R²=0.0554, P=0.010.4.2.3 plasma concentrations of benazeprilat versus decreasing deference of systolic pressure: R=0.036, R²=0.0013, P=0.694.4.2.4 plasma concentrations of benazeprilat versus decreasing deference of diastolic pressure: R=-0.018, R²=0.0003, P=0.846.5.SafetyNo significant clinical abnormality was found in all the indexs observed. All volunteers came back spontaneously with no adverse reaction.â…£Discussion and Conclusion1. In Chinese healthy male volunteers, benazepril was rapidly absorbed and almost completely metabolized to benazeprilat, which had much greater ACE inhibitory activity than benazepril. Peak plasma concentration of benazeprilat was reached quickly to bring into fullplay. T_max of benazepril and benazeprilat was in accordance with those reported in other similar studies. Compared with results found in foreign studies, AUC and C_max of benazeprilat and benazepril were positively related with dosage from 5 to 20mg. T_1/2 of benazepril and its metabolite in Chinese young men were longer than those in western people. It may be because of the increase of dosage and plasma concentration.2. In this single-dose study, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2-4 houres after dosing. The antihypertensive effect of a single dose persisted for 24 houres. Changes of the antihypertionsive effect were later than those of plasma concentrations. 3. Good tolerance and safety profile were observed in the giving dose. No significant clinical adverse reaction was observed.4. Compared with benazepril, its active metabolite benazeprilat has a chief effect on antihypertension. Compared with other ACE inhibitors without active metabolite, benazepril. HCL works slowly but lastly.