Influence of chronic kidney disease and haemodialysis treatment on pharmacokinetics of nebivolol enantiomers

Abstract

AIMThe present study evaluated the pharmacodynamics and pharmacokinetics of nebivolol enantiomers in patients with chronic kidney disease (CKD) and in patients undergoing haemodialysis. METHODSForty-three adult patients were distributed into three groups: healthy volunteers and hypertensive patients with normal kidney function (n = 22); patients with stage 3 and 4 CKD (n = 11); and patients with stage 5 CKD undergoing haemodialysis (n = 10). The subjects received a single oral dose of 10 mg racemic nebivolol. Serial blood samples were collected up to 48 h after administration of the drug and heart rate variation was measured over the same interval during the isometric handgrip test. The nebivolol enantiomers in plasma were analysed by liquid chromatography-tandem mass spectrometry. RESULTSThe pharmacokinetics of nebivolol is enantioselective, with a greater plasma proportion of l-nebivolol. CKD increased the area under the concentration-time curve (AUC) of l-nebivolol (6.83 ng.h ml -1 vs. 9.94 ng.h ml -1 ) and d-nebivolol (4.15 ng.h ml -1 vs. 7.30 ng.h ml -1 ) when compared with the control group. However, the AUC values of l-nebivolol (6.41 ng.h ml -1 ) and d-nebivolol (4.95 ng.h ml -1 ) did not differ between the haemodialysis and control groups. The administration of a single dose of 10 mg nebivolol did not alter the heart rate variation induced by isometric exercise in the investigated patients. CONCLUSIONSStage 3 and 4 CKD increases the plasma concentrations of both nebivolol enantiomers, while haemodialysis restores the pharmacokinetic parameters to values similar to those observed in the control group. No significant difference in heart rate variation induced by isometric exercise was observed between the investigated groups after the administration of a single oral dose of 10 mg nebivolol. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Chronic kidney disease decreases the nonrenal clearance of drugs as a result of the accumulation of uraemic toxins, which reduce the activity of cytochrome P 450 (CYP) isoforms and transporters.• Haemodialysis eliminates uraemic toxins and restores the activity of CYP isoforms. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 83-91 83

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