PubMed · 613874
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M A Duvelleroy. [Anesthesia and continuous flow].. https://pubmed.ncbi.nlm.nih.gov/613874/
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Telazol, a 1:1 combination of tiletamine HCl and zolazepam HCl, is an anesthetic and immobilizing agent that has been in use in veterinary medicine and animal field studies for more than a decade. No information is available, however, regarding the effects of Telazol, or its constituents, on hepatic cytochromes P450. The purpose of the present study was to assess the effect of Telazol on the rat hepatic cytochrome P450 system. Adult male rats were given a single intraperitoneal injection of Telazol dose at a of 20, 40, 80, or 120 mg/kg body weight (six rats/dose), while control rats received the vehicle only. Animals were killed 24 hr later, and hepatic microsomes were prepared. Treatment with Telazol resulted in dose-dependent increases in benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Ethoxyresorufin O-deethylase, p-nitrophenol hydroxylase, and testosterone 6 beta- and 7 alpha-hydroxylase activities were essentially unaltered at all doses of the drug. Densitometric quantitation of immunoblots probed with polyclonal antibody against cytochrome P450 2B1 indicated a 17-fold increase in the hepatic level of cytochrome P450 2B1 for rats treated with the highest dose of Telazol. In contrast, the level of cytochrome P450 2B2 was increased slightly but not significantly. In the presence of 0.5 mg of anti-cytochrome P450 2B1 IgG/nmol P450, benzyloxyresorufin O-dealkylase activity was inhibited by 92% in hepatic microsomes prepared from a rat treated with Telazol at a dose of 120 mg/kg compared with only 25% inhibition in hepatic microsomes from a control rat. In summary, the results demonstrate that Telazol specifically induced expression of the cytochrome P450 2B isozymes in rats.
The effects of loreclezole on the function of the gamma-aminobutyric acid type A (GABAA) receptor complex in rat cerebral cortical membrane preparations were compared with those of propofol and diazepam. Loreclezole and propofol modulated [3H]muscimol binding and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to washed and unwashed membranes with potencies and efficacies greater than those of diazepam. Loreclezole and propofol enhanced [3H]flunitrazepam binding to washed membranes with efficacies lower than those of GABA and muscimol. Both loreclezole and propofol showed biphasic effects on [35S]TBPS binding to washed membranes: at low concentrations (5 to 10 microM), both drugs, with different efficacies, enhanced [35S]TBPS binding whereas, at higher concentrations (30 to 100 microM), they inhibited this biochemical parameter. In contrast, diazepam enhanced [35S]TBPS binding to washed membranes at all concentrations tested. The combination of loreclezole with GABA, at a concentration (0.3 microM) that only slightly increased [35S]TBPS binding to washed membranes, reversed the increase in binding elicited by loreclezole (5 to 10 microM) and significantly potentiated the inhibitory effect exerted by higher concentrations (30 to 100 microM) of this drug. Similar effects were observed with the combination of GABA and propofol. However, GABA had no effect on the enhancement of [35S]TBPS binding induced by diazepam. The ability of GABA to reverse and potentiate the effects of loreclezole and propofol on [35S]TBPS binding to washed membranes was shared by pentobarbital (200 microM) and alphaxalone (3 microM). These anesthetics showed greater efficacies in combination with pentobarbital (200 microM) and alphaxalone (3 microM). These anesthetics showed greater efficacies in combination with propofol than with loreclezole. These results suggest that, unlike diazepam, loreclezole and propofol may activate the receptor-associated Cl- channel in the absence of GABA. Furthermore, the difference in the pharmacological profiles of loreclezole and propofol may result from their different effectiveness in activating the receptor Cl- channel directly.
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