The distribution of the metabolites in liver and kidney at various times after a single oral dose was investigated in rats under the same test conditions as used by Klein (1987a). The metabolites were extracted from lyophilized organs with water and methanol, further purified by HPLC and thin-layer chromatography and identified by comparative HPLC with authentic reference compounds in at least two independent chromatographic systems and also by mass and 1H-nuclear magnetic resonance spectroscopic techniques. The metabolites found in the kidney were identical to those identified in urine. Triazinone was not found in the excreta and may have undergone further biodegradation before elimination via the kidney or the bile. The relative amounts of those biotransformation products formed by oxidative mechanisms (e.g. 6-chloronicotinic acid) increased in the liver during the test period. In kidney, the relative amount of the more polar compounds decreased with time (6-chloronicotinic acid and its glycine conjugate), while the amounts of the olefinic metabolite and the mono-hydroxylated derivative 4-hydroxyimidacloprid showed a relative increase. The proportion of the parent compound decreased slowly as it was metabolized (Karl & Klein, 1992).
The main site of action of diazepam, as with other benzodiazepines, is at the -aminobutyric acid (GABA) receptor. The GABAA receptor is a ligand-gated chloride ion channel and part of a superfamily of receptors which also includes the nicotinic acetylcholine receptor and the glycine receptor (Ortells & Lunt, 1995). GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. Benzodiazepines including diazepam alter GABA binding at the GABAA receptor in an allosteric fashion but these drugs do not directly activate the receptors (Charney et al., 2001), which may account in part for their safety. Therefore the benzodiazepines may be envisaged as potentiating the effects of GABA receptors in the central nervous system (Costa & Guidotti, 1979). Thus, the benzodiazepines potentiate the endogenous control of the central nervous system against hyper-excitation (Sellström, 1992) and inhibit calcium channels (Rampe et al., 1987). The discovery of the specific benzodiazepine receptors in the central nervous system has also resulted in the development of an effective specific antagonist (flumazenil) (see Volume I of this series). The GABAA receptor is composed of five subunits and a number of these have been cloned. It is probable that the majority of receptors are composed of , and subunits but other subunits also exist (, , ). It has been suggested that the various actions of the benzodiazepines may be mediated by different GABAA receptor subtypes (see reviews by Johnston, 1996 and Sieghart & Sperk, 2002).
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