BACKGROUND: Nebivolol (N) is believed to be a unique cardiovascular agent studied worldwide for the treatment of HTN, CHF and other cardiovascular conditions owing to its vascular endothelial nitric oxide modulating capabilities and its highly selective  1antagonism. It is extensively metabolized with Ͻ0.1% of unchanged nebivolol excreted in urine. The present study examined what effect, if any, renal impairment has on oral N or its separate enantiomers.METHODS: Twenty-one subjects were divided into 3 renal impairment categories (mild, moderate, severe) based upon either measured (24-hour urine collection) or calculated (by Cockroft-Gault equation) creatinine clearance. Four healthy subjects, matched for age, gender, weight, and smoking habit, were selected as a control group.RESULTS: N (5 mg) was well tolerated with C max and T max being comparable across renal function classifications. Similar results were seen for the enantiomers and the active nebivolol glucuronide metabolites.
Background Nebivolol (N) is considered a unique racemic cardio‐selective β1‐antagonist with vascular endothelial nitric oxide modulating capabilities that undergoes extensive metabolism to active moieties via the CYP2D6 enzymatic pathway. Fluoxetine (F), one of the most studied potent inhibitors and substrates of CYP2D6 enzyme used clinically, was selected to assess the potential interactions with N. Methods Ten CYP2D6 extensive metabolizers (EM) received an oral 10 mg dose of N on Day 1, an oral 20 mg dose of F QD on Days 8 through 27, and 10 mg N plus 20 mg F on Day 28. PK estimates for N were assessed. Results (see Table) Co‐administration of N with F was well tolerated. Conclusions The results confirm N's reliance on the CYP2D6 enzymatic pathway for elimination. The elevated N plasma concentrations seen with the co‐administration of F were considerably lower than the clinically safe and well‐tolerated levels of N alone previously observed in poor metabolizer subjects (AUC∞: 614 ng·hr/mL; Cmax: 9.21 ng/mL). Clinical Pharmacology & Therapeutics (2005) 77, P38–P38; doi: Parameter Day 1 Day 28 Ratio 90% CI AUC∞ (ng hr/mL)13.8792.336.024.57–7.91Cmax (ng/mL)2.335.452.271.83–2.80Tmax (hr)1.302.602.001.58–2.42t1/2 (hr)12.5117.451.401.07–1.72Cl/F (L/hr)787.0142.90.180.014–0.35
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