Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their active metabolites.
The pharmacokinetics of benazepril, enalapril, and their active metabolites (benazeprilat and enalaprilat) were compared after a single administration of each product by the oral route at the recommended dosage (0.5 mg/kg for both drugs) in the dog before and after moderate experimental renal impairment. Ten dogs were randomly assigned to 2 groups of 5 animals in a 2-period crossover design for angiotensin-converting enzyme inhibitor administration. Renal failure was surgically induced by right nephrectomy and electrocoagulation of the remaining kidney. Renal mass reduction induced a significant decrease (P < .001) in glomerular filtration rate (GFR) (1.7 +/- 0.3 versus 3.3 +/- 0.7 mL/kg/minute). No significant differences before and after surgery were observed for enalapril and benazepril kinetics. The area under the curve (AUC) for enalaprilat increased after surgery from 23.6 +/- 14.7 to 42.4 +/- 20.9 micrograms.minute/mL (P < .01). Mean peak plasma concentration (Cmax) was increased in the impaired dogs (59.1 +/- 23.3 versus 43.9 +/- 32.9 ng/mL), but this variation was not significant (P > .05). Renal failure had no significant effect on AUC for benazeprilat (13.8 +/- 9.8 versus 14.9 +/- 5.0 micrograms.minute/mL) (P > .05), but Cmax decreased significantly (from 55.0 +/- 26.4 to 31.9 +/- 17.7 ng/mL) (P < .05). Multiple regression analysis showed that both GFR and AUC for enalapril were highly significant variables that explained the variation in AUC for enalaprilat (R2 = .86, P < .001) but not for benazeprilat (R2 = .12, P > .05). The results of this study indicate that exposure to enalaprilat, but not to benazeprilat, is increased in dogs with subclinical renal impairment.
Département des Sciences biologiques et fonctionnelles, Ecole Nationale Vétérinaire, Toulouse, France. h.lefebvre@envt.fr
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D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001774:Blood Chemical Analysis / Q000662:veterinary; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D003287:Contrast Media / Q000737:chemistry; D018592:Cross-Over Studies; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D004656:Enalapril / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000662:veterinary; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000662:veterinary; D007483:Iothalamic Acid / Q000737:chemistry; D011897:Random Allocation; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism / Q000662:veterinary*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D003287:Contrast Media; D007483:Iothalamic Acid; D004656:Enalapril; C044946:benazepril