Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam.
We studied the pharmacokinetics of a single 0.5-mg i.v. dose of chlordesmethyldiazepam in 8 patients with liver disease and in 12 age-matched healthy controls. The kinetics were also studied of a single 1-mg oral dose in the patients with liver disease. After i.v. administration the kinetics of total chlordesmethyldiazepam in patients with liver disease differed from those in controls: elimination half-life was almost twice that in controls (395 and 204 h), as a consequence of a marked reduction in total clearance (0.13 and 0.25 ng.ml-1.h-1), whereas the apparent volume of distribution was similar in patients and controls (4.7 and 3.9 l/kg-1). The free fraction of the drug in patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed clearance in the patients was one-fifth (1.8 and 10.5 ng ml-1.kg-1) and volume of distribution one-half (65.0 and 118.4 l.kg-1) that in controls. The systemic availability of oral chlordesmethyldiazepam was high (110%) in spite of a relatively slow absorption rate. These results indicate a need for caution in the administration of chlordesmethyldiazepam to patients with liver disease.
Bareggi
S R
SR
Department of Pharmacology, Chemotherapy and Medical Toxicology, Università degli Studi, Milan, Italy.
Pirola
R
R
Potvin
P
P
Devis
G
G
D000284:Administration, Oral; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001569:Benzodiazepines; D005260:Female; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D007275:Injections, Intravenous; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D003708:Nordazepam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010599:Pharmacokinetics
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001569:Benzodiazepines; D003708:Nordazepam; C013434:chlordesmethyldiazepam