Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam

Abstract

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.

Quantification of chlordesmethyldiazepam by liquid chromatography–tandem mass spectrometry: application to a cloxazolam bioequivalence study

“…: 31868-18-5) (Miyaguchi et al, 2006). After oral administration of cloxazolam, CDDZ peak plasma concentration occurs between 2 and 3 h. The CDDZ biphasic-pattern elimination half-life is variable and ranges from 65.9 to 204 h (Bareggi et al, 1986b(Bareggi et al, , 1988a(Bareggi et al, , 1995.…”