Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs

Abstract

The clinical effects and pharmacokinetics of medetomidine (MED) and its enanti-omers, dexmedetomidine (DEX) and levomedetomidine (LEVO) were compared in a group of six beagle dogs. The dogs received intravenously (i.v.) a bolus of MED (40 microg/kg), DEX (20 and 10 microg/kg), LEVO (20 and 10 microg/kg), and saline placebo in a blinded, randomized block study in six separate sessions. Sedation and analgesia were scored subjectively, and the dogs were monitored for heart rate, ECG lead II, direct blood pressure, respiratory rate, arterial blood gases, and rectal body temperature. Blood samples for drug analysis were taken. Peak sedative and analgesic effects were observed at mean (+/- SD) plasma levels of 18.5 +/- 4.7 ng/mL for MED40, 14.0 +/- 4.5 ng/mL for DEX20, and 5.5 +/- 1.3 ng/mL for DEX10. The overall level of sedation and cardiorespiratory effects did not differ between MED40, DEX20 and DEX10 during the first hour, apparently due to a ceiling effect. However, the analgesic effect of DEX20 lasted longer than the effect of the corresponding dose of racemic medetomidine, suggesting greater potency for dexmedetomidine in dogs. Levomedetomidine had no effect on cardio-vascular parameters and caused no apparent sedation or analgesia. The pharmacokinetics of dexmedetomidine and racemic medetomidine were similar, but clearance of levomedetomidine was more rapid (4.07 +/- 0.69 L/h/kg for LEVO20 and 3.52 +/- 1.03 for LEVO10) than of the other drugs (1.26 +/- 0.44 L/h/kg for MED40, 1.24 +/- 0.48 for DEX20, and 0.97 +/- 0.33 for DEX10).

Dog UDP-Glucuronosyltransferase Enzymes of Subfamily 1A: Cloning, Expression, and Activity

“…Racemic medetomidine is used also as a veterinary drug to treat dogs (Kuusela et al, 2000), and the results with DLM indicate that both medetomidine enantiomers can be glucuronidated in this tissue, as previously reported (Kaivosaari et al, 2008). Nevertheless, while human UGT1A4 was the most active enzyme in dexmedetomidine glucuronidation (Kaivosaari et al, 2008) (Fig.…”

Regio- and Stereospecific N-Glucuronidation of Medetomidine: The Differences between UDP Glucuronosyltransferase (UGT) 1A4 and UGT2B10 Account for the Complex Kinetics of Human Liver Microsomes

“…Levomedetomidine is practically devoid of pharmacological activity (MacDonald et al, 1991;Savola and Virtanen, 1991). In veterinary use for dogs and cats, medetomidine was originally used as a racemic mixture (Ansah et al, 2000;Kuusela et al, 2000), but it was recently launched as a formulation containing only the pure dextroenantiomer.…”

Influence of MK-467, a Peripherally Acting α2-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs

“…Dexmedetomidine has also been shown to dose dependently reduce its own clearance in humans, a phenomenon mediated via reduced cardiac output (Dutta et al, 2000). Likewise, dexmedetomidine has been suggested to alter its own pharmacokinetics in dogs (Salonen et al, 1995;Kuusela et al, 2000). It also reduces the distribution of thiopental in humans (Bührer et al, 1994).…”

“…Therefore, we decided to evaluate the plasma concentrations of intravenously administered dexmedetomidine in dogs when coadministered three different doses of MK-467. The focus was on the 1st h after drug administration, when dexmedetomidine is known to have its peak cardiovascular and sedative effects (Pypendop and Verstegen, 1998;Kuusela et al, 2000;Honkavaara et al, 2011;Restitutti et al, 2011). We hypothesized that MK-467 would reduce the exposure to dexmedetomidine because of an improved cardiac index compared with dexmedetomidine alone.…”