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

Abstract

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.

A Fixed Moderate-dose Combination of Tiletamine+Zolazepam Outperforms Midazolam in Induction of Short-term Immobilization of Ball Pythons (Python regius)

“…Pharmacokinetic data are not available for tiletamine or zolazepam in reptiles, presenting a potential topic for future research. It also remains to be determined whether reptiles metabolize tiletamine and zolazepam primarily through the kidneys as has been demonstrated for mammals [68]. This lack of pharmacokinetic data and pKa studies in reptiles presents a considerable limitation to our study and other investigations of the performance of anesthetic compounds in reptiles.…”

“…This highly variable recovery time and lingering sedation (as well as the variable induction length) between individual snakes receiving 3 mg/kg of tiletamine+zolazepam may be due to differing pharmacokinetic clearance mechanisms of tiletamine and zolazepam. In pigs, tiletamine is metabolized much faster than zolazepam, and zolazepam metabolites retain more pharmacologic activity than tiletamine metabolites, thus prolonging the sedative effect of the drug combination beyond its dissociative effects [68].…”

A fixed moderate-dose combination of tiletamine+zolazepam outperforms midazolam in induction of short-term immobilization of ball pythons (Python regius)

“…This highly variable recovery time and lingering sedation (as well as the variable induction length) between individual snakes receiving 3 mg/kg of tiletamine+zolazepam may be due to differing pharmacokinetic clearance mechanisms of tiletamine and zolazepam. In pigs, tiletamine is metabolized much faster than zolazepam, and zolazepam metabolites retain more pharmacologic activity than tiletamine metabolites, thus prolonging the sedative effect of the drug combination beyond its dissociative effects [ 70 ].…”

Effects of a non-competitive N-methyl-d-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish

“…NMDA receptors appear to be the prime known pharmacological target of tiletamine, since the drug does not seem to modulate other (e.g., adrenergic, sigma-, glycine-, kainate-, quisqualate-or dopamine) brain receptors (Chen et al, 1969;Rao et al, 1991b). Tiletamine has sufficient metabolic stability in the body (Chen et al, 1969;Kumar et al, 2014), but shows a rapid onset of neuroactive action, evoking feelings of dissociation and hallucinations clinically (Morris and Wallach, 2014). The drug does not cause tolerance (Chen et al, 1969), and behaviorally resembles ketamine and PCP in drug discrimination tasks in rats (Browne and Welch, 1982;de la Pena et al, 2012;de la Pena et al, 2013).…”