group but not in the control group. Furthermore, the pharmacokinetics of thiopen-
tone in phenobarbitone-treated animals following a typical exponential decay
consistent with first order elimination and half-life and clearance values approxi-
mated those previously reported for mixed-breed dogs (Sams and Muir 1988 ).
Given the known importance of cytochrome P450 in determining the elimination
of barbiturates in other species, these findings are consistent with a lack in Grey-
hounds of one or more cytochrome P450 isoforms responsible for thiobarbiturate
(but not pentobarbitone) metabolism in dogs.
Elimination of several other drugs is also reported to be significantly slower in
Greyhounds compared with other canine breeds. These include propofol (Zoran
et al. 1993 ), antipyrine (KuKanich et al. 2007 ), ketoconazole (KuKanich and Borum
2008b) and celecoxib (Hunter et al. 2005 ), all of which are metabolised by cyto-
chrome P450. On the other hand, methadone, a substrate for cytochrome P450 3A,
was reported to have a higher clearance in Greyhounds compared with Beagles
(KuKanich and Borum2008a), suggesting that not all cytochrome P450 isoforms
are deficient. Amikacin, a polar drug which is cleared primarily unchanged by the
kidney, is reported to have a 30% lower plasma clearance in Greyhounds compared
with Beagles, although the volume of distribution is also lower in Greyhounds such
that elimination half-life is similar between the breeds. Morphine, which is cleared
primarily by glucuronidation and also by sulphation, also showed a somewhat lower
clearance by about 30% in Greyhounds compared with published values for other
dogs, although again the elimination half-life was similar because of a lower volume
of distribution (KuKanich and Borum2008b). Finally, the depolarising muscle
relaxant succinylcholine, which is metabolised by plasma pseudocholinesterase,
has a similar duration of muscle relaxant effect in Greyhounds compared with
mixed-breed dogs (Curtis and Eicker 1991 ). The same study also demonstrated
similar pseudocholinesterase activities in plasma collected from the same dogs
regardless of breed.
In vitro studies have explored the molecular basis for slower metabolism of
propofol, a non-barbiturate ultra-short acting anaesthetic, in Greyhounds (Court
et al. 1999 ; Hay Kraus et al. 2000 ). An in vitro assay using dog liver microsomes
was developed to measure the rate of cytochrome P450 mediated oxidation of
propofol to 4-hydroxyprofol, the major propofol metabolite in dogs (Court et al.
1999 ). Using liver microsomes from male Greyhound, Beagle, and mixed-breed
dogs (five animals each), it was found that the rate of propofol oxidation was about
3 times slower in Greyhound liver compared with Beagle liver, while mixed-breed
dog liver activities were intermediate (Fig. 3 ). Enzyme kinetic studies showed
similarly that the difference primarily was not associated with altered enzyme
affinity (based onKmvalues) but was the result of lowerVmaxvalues in the
Greyhound livers (Hay Kraus et al. 2000 ). This suggests that Greyhounds may
have lower expression of the main cytochrome P450 responsible for propofol
hydroxylation in dogs. Further work using P450-specific chemical and antibody
inhibitors indicated that this isoform is probably CYP2B11, a major isoform
expressed in dog liver. However, as yet it is unclear whether a genetic polymor-
phism accounts for low CYP2B11 expression, and whether low CYP2B11
56 C.M. Mosher and M.H. Court