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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\u2010Dawley 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<jats:italic>in vitro<\/jats:italic>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\u2010systemic 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 (+ &gt; \u2010) 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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