I The pharmacokinetics of clobazam and its biotransformation product N-desmethylclobazam were investigated after single and multiple doses in normal subjects. 2 The relevant physicochemical properties of clobazam were measured and are presented. Different assay methods (radiochemical, fluorimetric and gas chromatographic) were applied and the results correlated. 3 After single doses the pharmacokinetic profile of clobazam includes time to peak levels 1-4 h after dosing, peak levels increasing linearly with the logarithm of dose, and terminal half-lives of about 18 hours. At least 87% of an oral dose is absorbed, as indicated by urinary recovery of labelled material. 4 In multiple-dose studies unchanged clobazam levelled off at minimum steady-state concentrations within one week of dosing. During 28 d of medication N-desmethylclobazam accumulated to near steady-state levels about eight times higher than those of the unchanged compound. 5No pharmacokinetic interactions were discovered between clobazam and the antidepressant nomifensine.

No abstract

I The present study was designed to investigate both pharmacodynamic and pharmacokinetic interactions of clobazam and alcohol. 2 Eight healthy male volunteers participated in an intraindividual Latin square comparison of (a) clobazam 20 mg; (b) placebo; (c) alcohol + placebo; and (d) alcohol + clobazam 20 mg. Alcohol was administered orally in quantities individually calculated to yield serum alcohol concentrations of about 1000 gg/ml. The comparison of treatments (a) against (b) and (c) against (d) was double blind. Drugfree periods between the trials were 7 days. 3 Pharmacodynamic assessments were carried out before and 2, 3 and 5 h after administration using a series of tests of choice reaction performance, simple reaction time, two-hand coordination and body sway, together with self ratings, side-effects lists, vital signs and blood chemistry. 4 Blood samples were obtained before and 50, 100, 160, 220, 280, 340 and 1440 min after administration. Serum levels of clobazam and alcohol were determined by gas chromatography. 5The dynamic results show significant differences between the alcohol and non-alcohol treatments and no significant difference either between clobazam and placebo, or between alcohol alone and alcohol + clobazam. Numerically, however, the detrimental effects of the combination were consistently stronger, indicating a possible pharmacodynamic interaction. 6 A pharmacokinetic interaction was found, as the serum clobazam levels were higher after combined administration of clobazam and alcohol than after clobazam alone. An enhanced absorption of clobazam and a reduced distribution volume may explain this finding which is comparable to findings obtained with diazepam and alcohol (Hayes et al., 1977). 7 It is concluded that combined ingestion of clobazam and alcohol is likely to be more hazardous than that of alcohol alone.

normal English and German sUbjectsA major problem in quantitating dosage equivalence of diuretics is the variation in response between subjects in normal populations as well as in patients with edema. There are also wide variations in response within subjects. Some of this variation can be explained by measurement of factors present prior to drug administration. Known examples are the correlation between the aldosterone secretion rate before treatment and the diuretic response to ethacrynic acid,5 the correlation Supported by Hoechst Phannaceuticals, England.

1. A radioimmunoassay (RIA) has been developed for determination of both nomifensine and total nomifensine (nomifensine + conjugated nomifensine) in serum, plasma, and urine. 2. Antibodies were prepared in rabbits by immunization with N‐(8‐Nomifensine) succinamic acid‐ bovine serum albumin. 3H‐labelled drug was used as tracer. Separation of free from antibody‐bound nomifensine was carried out using dextran‐ coated charcoal. For determination of total nomifensine, the acid‐ labile conjugate was split by acidification. 3. The limit of detection for nomifensine is 300 pg/ml plasma and the cross‐reactivity of the metabolites is less that 1%. The influence of conjugated nomifensine on the results of nomifensine can be corrected. 4. Pharmacokinetics of nomifensine were determined in healthy volunteers after oral administration of 100 mg 14C‐labelled drug. Peak levels of 14C radioactivity (2,150 ng/ml), total nomifensine (1,252 ng/ml) and nomifensine (53 ng/ml) appeared within 1.5‐2 h; the half‐life of elimination from plasma was 1.5‐2 hours. The advantages of this routine method are high sensitivity, the requirement of small amounts of plasma, and simple handling.