Most of the studied individuals were women, and the proportion of elderly with heart disease classified as PM was smaller than what is usually found among Caucasian populations.
The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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
Nebivolol is a third-generation β1-adrenoceptor blocker with β3 agonistic properties (AR). It has a low oral bioavailability that is speculated to be due to its hepatic first-pass metabolism. Inflammation is known to suppress the clearance of drugs with efficient hepatic metabolism. However, inflammation does not influence nebivolol clearance. Therefore, we looked into the mechanism involved in the drug's low bioavailability and stereoselectivity. Single 1 mg/kg i.v. or intraperitoneal (i.p.) or 2 mg/kg oral doses were administered to male Sprague-Dawley rats and the plasma nebivolol concentration was measured using chiral and achiral assays. The passage of nebivolol enantiomers through the gut was also measured using everted rat sacs. The serum protein binding of the enantiomers was studied in vitro using the ultrafiltration method. Plasma nebivolol concentrations were significantly lower after p.o., but not after i.p., compared with i.v. doses suggesting the gut as the site of pre-systemic loss. Approximately 50% of the enantiomers were lost during 90 min incubation in the presence of gut. Only 0.1% of the added drug crossed the gut wall with no evidence of stereoselectivity. Thus stereoselectivity in the pharmacokinetics of nebivolol (+ > -) is likely at the level of plasma protein binding. The low nebivolol bioavailability is due to its loss in the gut as well as its limited permeability through the intestinal wall.
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