Kinetics and metabolism of clobazam in animals and man.

Abstract

I The pharmacokinetic behaviour of the psychotropic drug clobazam, a 1,5 benzodiazepine, and its metabolism were studied with the "4C-labelled compound in rats, dogs, monkeys and man. The absorption was practically complete in all three animal species. Clobazam was not excreted in the unchanged form by all species. The main metabolite in plasma of monkeys, dogs and man was N-demethylclobazam. The metabolites were partially in the conjugated form.2 The binding to serum proteins (concentration range 0.05-10 jg/ml serum) amounted to between 66% (in rats) and 85% (in man). The maximal levels of total radioactivity (original compound and metabolites) in blood were 0.24 + 0.043 ig Equ/ml (2-4 h) in doses and 0.67-0.82 jg Equ/ml (0.5-1 h) in rhesus monkeys. These levels were markedly higher than those in rats with values of 0.064 + 0.012 jig Equ/ml (-0.5 h). The elimination of radioactivity from blood occurred in two phases.3 After repeated daily administration of oral doses, the 24-h blood levels accumulated in rats to about three times the initial value. In dogs the 24-h serum concentrations remained practically unchanged. Long-term treatment with clobazam in monkeys neither caused enzyme induction nor other processes retarding metabolism and elimination. 4 Both after a single oral and intravenous dose, more than two-thirds of the radioactivity administered to rats was excreted with the faeces. Dogs, however, excreted about three-quarters of the radioactivity with the urine, irrespective of the route of administration. In monkeys, the excretion also occurred mainly in the urine. In all three species, renal excretion was similarly rapid to that from blood or plasma. 5 Apart from gastro-intestinal tract, liver and kidneys, the distribution in rats and dogs was remarkably even within the range of maximal blood levels. In the rat brain, the concentration amounted to only one-third of that in the blood. Special accumulations were not found. In dogs, the concentration in the brain was as high as that in the blood. 6 In rats, kinetics and metabolism were not significantly changed by pregnancy. 7 For metabolism studies in the four species (man, monkey, dog and rat) urine and faeces (and in some cases also serum) were examined after a single dose or repeated administration. The number and kind of metabolites detected in the individual species were partially different. In autoradiographic studies, exceptionally up to 14 radioactive spots were found for clobazam. 8 The structures of the metabolites were elucidated by independent methods, mainly mass spectrometry. In addition to the original substance, eight metabolites were identified for clobazam amounting to 70-90%/o of the total number of metabolites, depending on the species.The two most important chemical changes of clobazam during metabolism are dealkylation and hydroxylation. Dealkylation at nitrogen-(I), particularly pronounced in the species dog, does not differ between the 1,4-and 1,5-benzodiazepines. The difference in metabolism is only pronounced in oxidative deco...

Clobazam plasma concentrations: pharmacokinetic study in healthy volunteers and data in epileptic patients.

“…The pharmacokinetics and metabolism of CLB have been investigated in different animal species (Volz, Christ, Kellner, Fehlhaber, Gantz, Hajdu & Cavagna, 1979) and in man (Rupp, Badian, Christ, Hajd, Kulkarni, Taeuber, Viehlein, Bender & Vanderbeke, 1979;Vallner, Needham, Jun, Brown, Stewart, Kotzan & Honigberg, 1978) using different techniques. However, in the first reported human study (Vallner et al, 1978) the fluorometric method used was not able to distinguish between CLB and its desmethylmetabolite and in another study (Rupp et al, 1979) no detailed information was given regarding the subjects, the plasma sampling and the kinetic analysis.…”

In Vitro and in Vivo Inhibitory Effect of Stiripentol on Clobazam Metabolism

“…Indeed, 4Ј-hydroxynorclobazam (OH-NCLB) mean plasma concentrations decreased on average 83%, whereas those of CLB and norclobazam (NCLB) significantly increased on average 173%. It is known that CLB can be first either demethylated to NCLB or hydroxylated to 4Ј-hydroxyclobazam (OH-CLB); then, NCLB and OH-CLB can be transformed to OH-NCLB (Volz et al, 1979). Because STP is known to be an inhibitor of several P450s (Tran et al, 1997), it might be responsible for the inhibition of the metabolism of CLB.…”

Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients.

“…Its metabolism has been studied in man, rat, dog and monkey (Volz et al, 1979). Up to fourteen metabolites have been identified, the most important being the pharmacologically active N-desmethylclobazam.…”