Plasma protein binding of ketanserin and its distribution in blood

The in vitro plasma protein binding and distribution in blood of ketanserin ((+/-)-3-[2-[4-(4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied in rats, dogs and humans. Plasma protein binding of ketanserin amounted to 95.1% in healthy subjects, 88.1% in dogs and 98.8% in rats. Its blood to plasma concentration ratio was 0.70 in humans, 0.78 in dogs and 0.65 in rats. Plasma protein binding of ketanserin-ol, the main plasma metabolite of ketanserin, was 81.2% in humans and its blood to plasma concentration ratio was 1.04. The plasma protein binding of both ketanserin and ketanserin-ol was highly dependent on pH. Albumin was by far the main binding protein for ketanserin in human plasma and binding was independent of the ketanserin concentration within a very wide range. Plasma protein binding of ketanserin in elderly hypertensive patients was not significantly different from that in healthy adults. In chronic renal failure patients, whether on haemodialysis or not, the free ketanserin fraction was 40% higher than in healthy subjects. High therapeutic levels of ketanserin (0.25 microgram/ml) did not influence the plasma protein binding of diphenylhydantoin, hydrochlorothiazide, imipramine, ketoconazole, propranolol or warfarin. Out of 12 drugs, only tolbutamide at therapeutic concentrations decreased significantly the plasma protein binding of ketanserin. However, the resulting 5-20% increase of the free ketanserin fraction is hardly clinically relevant.