Ketanserin pharmacokinetics in patients with renal failure.

Abstract

1 The pharmacokinetics of ketanserin and its major metabolite ketanserin-ol were investigated after a single oral dose of 40 mg and after chronic oral administration of 20 or 40 mg twice daily for 10 days in 12 patients with chronic renal insufficiency of whom six were on intermittent haemodialysis. Plasma protein binding of ketanserin was measured in these 12 patients and in eight healthy volunteers. 2 In both dialysis and non-dialysis patients the terminal half-life of ketanserin (mean + s.d.) was prolonged compared with that reported previously for healthy volunteers (28 ± 4 h vs 18 ± 4 h). This may be explained by a lowered renal clearance of ketanserin-ol from which ketanserin is partly regenerated. 3 In patients with chronic renal insufficiency plasma ketanserin concentrations were similar to those found in healthy subjects after the same dose. Plasma ketanserin-ol concentrations were elevated, resulting in a raised AUC ratio of ketanserin-ol to ketanserin as compared with healthy individuals (7.3 ± 4.0 vs 3.2 ± 0.7). 4 Urinary excretion of ketanserin was negligible in both dialysis and non-dialysis patients, and ketanserin-ol excretion was markedly lowered. 5 The plasma protein binding of ketanserin was slightly reduced in comparison with healthy volunteers (93.7 ± 1.0% vs 95.0 ± 0.2%). 6 A dose regimen of 20 mg twice daily appeared to be well tolerated in spite of less plasma binding in renal failure.

Clinical Pharmacokinetics of Ketanserin

“…In these subjects the 267 plasma protein binding, primarily to albumin, was 95%, which was higher than the blood cell binding (84%). However, a significant 50% increase of the free fraction to approximately 7.5% was observed in patients with hepatocellular and renal insufficiency (Barendregt et al 1990;Lebrec et al 1990;Meuldermans et al 1988b). For ketanserin-01 the plasma protein binding was 81 % and the blood/plasma concentration ratio 1.04.…”

“…Four studies involving a total of 55 patients were designed to study the pharmacokinetics of ketanserin in patients with renal disease (Barendregt et al 1990;Onoyama et al 1988;Proppe et al 1989;Zazgomik et al 1986). The degree of renal impairment ranged from moderate (mean serum creatinine level 230 ~mol/L; Onoyama et al 1988) to severe (mean serum creatinine level 699 ~mol/L; Barendregt et al 1990) and 15 patients required regular haemodialysis.…”

Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3‐(2‐Chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) or Dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1)

“…Ketanserin ( 5 ), a drug with affinity for multiple G protein‐coupled receptors, especially serotonin receptors, was discovered at Janssen Pharmaceutical in 1980 and classified as an antihypertensive by the World Health Organization. It has been used to reverse hypertension caused by protamine (which, in turn, was administered to reverse the effects of heparin overdose) and in cardiac surgery . Tritium ( 3 H) radioactively labeled 5 was used as a radioligand for the serotonin 5‐HT 2A receptor, for example, in receptor binding assays and autoradiography .…”