Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration-effect relationships in normotensive subjects.
1. This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha 1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5 micrograms kg-1 in young, normotensive males. 2. alpha 1-adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5-fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose-response curve for diastolic blood pressure. 3. Despite evidence of substantial alpha 1-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4. The degree of alpha 1-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P less than 0.05) and r = 0.78 for diastolic blood pressure (P less than 0.005). 5. In conclusion, abanoquil produced significant alpha 1-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.
Schafers
R F
RF
University Department of Medicine and Therapeutics, Stobhill General Hospital, Glasgow.
Elliott
H L
HL
Meredith
P A
PA
Miller
S H
SH
Reid
J L
JL
D000317:Adrenergic alpha-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D000634:Aminoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016037:Single-Blind Method; D044005:Tetrahydroisoquinolines
D000317:Adrenergic alpha-Antagonists; D000634:Aminoquinolines; D044005:Tetrahydroisoquinolines; D010656:Phenylephrine; C058534:abanoquil