Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects.
The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)
Kroboth
P D
PD
Center for Pharmacodynamic Research, Department of Pharmacy and Therapeutics, Upjohn Company, Kalamazoo, Michigan.
Maxwell
R A
RA
Fleishaker
J C
JC
Van Thiel
D H
DH
Smith
R B
RB
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001569:Benzodiazepines; C039668:adinazolam; C050132:mono-N-demethyladinazolam