Pharmacokinetic study in pigs and in vitro metabolic characterization in pig- and human-liver microsomes reveal marked differences in disposition and metabolism of tiletamine and zolazepam (Telazol).

1. An equal-dose combination of tiletamine and zolazepam (Telazol®) is used as a veterinary anesthetic. There also have been reports of human abuse of Telazol®. The pharmacokinetics and metabolic fate of tiletamine and zolazepam and the rationale for their administration as an equal-dose combination are unclear. 2. The single-dose pharmacokinetics of intramuscular tiletamine and zolazepam (3 mg/kg each) in 16 Yorkshire-crossbred pigs were determined. The metabolites of tiletamine and zolazepam in pig plasma and urine were identified by mass spectrometry. The metabolic stability of tiletamine and zolazepam and the kinetics of formation of their metabolites by pig- and human-liver microsomes were determined. 3. Higher concentrations of zolazepam were observed in pig plasma and it was cleared more slowly compared to tiletamine (apparent clearance: 11 versus 134 l/h; half-life: 2.76 versus 1.97 h). Three metabolites of zolazepam and one metabolite of tiletamine were identified in pig urine, plasma and in microsomal incubations. In vitro formation of each of these metabolites in microsomes was biphasic involving a high-affinity/low-capacity and a low-affinity/high-capacity enzyme. The in vitro metabolic stability of tiletamine was considerably lower compared to zolazepam. 4. These results collectively point to major pharmacokinetic and metabolic differences between the two components of this fixed-dose anesthetic combination.