Human pharmacokinetics and tolerability of L-365,260, a novel cholecystokinin-B antagonist.
A study was conducted to examine the tolerability and pharmacokinetics of single and multiple oral doses of L-365,260, a novel antagonist for type B cholecystokinin (CCK) receptors and to quantify effects of selective blockade of type B CCK receptors through treatment with L-365,260 on measures of anxiety, hunger, and cognitive performance. Healthy volunteers were given single oral doses of up to 50 mg of L-365,260 and multiple oral doses of up to 25 mg every 6 hours for 10 days. Plasma concentrations of L-365,260 were quantified by means of high-performance liquid chromatography. Anxiety and hunger were assessed by visual analog scale and the Spielberger State Anxiety Index. Cognitive testing was used to evaluate attention level and short-term memory. L-365,260 was rapidly absorbed and a biphasic pattern of elimination was demonstrated with a terminal half-life (t1/2) of 8 to 12 hours. The mean (n = 6) values for peak plasma concentration (C(max)) and time to peak concentration (t(max)) of L-365,260 were 503 ng/mL and 1.25 hours, respectively, after a single 50-mg oral dose. Accumulation of L-365,260 plasma concentrations was seen after the prescribed multiple-dose regimens. Steady state was achieved after 3 days of oral administration. L-365,260 had an acceptable tolerability profile after oral administration. No changes in measures of anxiety, hunger, or short-term memory were observed at doses of L-365,260 shown to have antagonist activity at the CCK-B receptor.
Grasing
K
K
Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick 08903-0019, USA.
Murphy
M G
MG
Lin
J
J
Swigar
M
M
Freedholm
D
D
Clarke
L
L
Zhang
J
J
Wolkowitz
O M
OM
Weingartner
H
H
Putnam
K
K
Seibold
J R
JR
D000284:Administration, Oral; D000328:Adult; D001007:Anxiety / Q000188:drug therapy; D001570:Benzodiazepinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003071:Cognition / Q000187:drug effects; D006801:Humans; D006815:Hunger / Q000187:drug effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D010671:Phenylurea Compounds
D001570:Benzodiazepinones; D010671:Phenylurea Compounds; C058121:L 365260