Rabbit drug metabolism

Smolarek, T.A., Higgings, C.V and Amacher, D.E. (1990a). Metabolism and cytotoxicity of acetaminophen in hepatocyte cultures from rat, rabbit, dog and monkey. Drug Metabolism and Disposition 18 659-663. 

Carlson, GP. (1981) Effect of alterations in drug metabolism on epinephrine-induced cardiac arrhythmias in rabbits exposed to methylchloroform. Toxicol. Lett., 9, 307-313... 

Rabbit strains may exhibit up to 20-fold variation, particularly in the case of hexobarbital, amphetamine, and aminopyrine metabolism. Relatively smaller differences between strains occur with chlorpromazine metabolism. Wild rabbits and California rabbits display the greatest differences from other rabbit strains in hepatic drug metabolism. 

R.L. Cram, M.R. Juchau, and J.R. Fouts, Differences in hepatic drug metabolism in various rabbit strains before and after pretreatment with phenobarbital. Proc. Soc. Exp. Biol. Med. 118 872, 1965. 

Traditionally, drug metabolism studies rely on the use of model systems to predict the intermediates and products of dmg metabolism in humans. For these purposes whole animal systems are in use, especially small laboratory animal models (e.g. rat, dog, cat, guinea pig, rabbit). In vitro studies are generally used to complement and specify the data obtained using perfused organs, tissue or cell cultures, and microsomal preparations. As discussed in more detail later, microorganisms can be used as model systems as well. 

MODIFICATIONS OF THE METHOD This method has been widely used for studying carbohydrate and lipid intermediary metabolism (Herling et al. 1998) as well as drug metabolism (Milne et al. 1997 and Milne et al. 2000, Vuppugalla 2004). Many variations have been reported predominantly with respect to the animal species used. Chaib et al. (2004) compared isolated perfused livers of rats with those of guinea pigs. Den Butter (1994) used livers from rabbits. Further modifications are related to the direction of perfusion via hepatic artery or portal vein or both simultaneously or in connection with the isolated jointly perfused small intestine (Stumpel et al. 1997 and Stumpel et al. 2000) as well as the continuous perfusion in a recirculated (see above) or open (non-recirculated) manner (Lopez et al. 1998). 

Arinc E, Adali O, Iscan M, et al. 1991. Stimulatory effects of benzene on rabbit liver and kidney microsomal cytochrome P-450 dependent drug metabolizing enzymes. Arch Toxicol 65(3) 186-190. 

Age effects in drug metabolism are illustrated in Figure 9.3, showing how the rabbit liver microsomes increase in activity with age. In this species, the level of microsomal monooxygenase activity in adults is reached in about 30 days. 

Bioreduction of ketones often leads to (he creation of an asymmetric center and. thereby, two possible stereoisomeric alcohols. " For example, reduction of acetophenone by a soluble rabbit kidney reductase leads to the enantiomeric alcohols (5)(-)- and (R)( + )-mcthylphen lcarbinol. with the (.V)(-) isomer predominating (3 1 ratio). The preferential formation of one stereoisomer over the other is termed product stereoselectivity in drug metabolism. " Mechanistically, ketone reduction involves a "hydride" transfer from the reduced nicotinamide moiety of the cofactor NADPH or NADH to (he carbonyl carbon atom of the ketone. It is generally agreed that this step proceeds with considerable stereoselectivity." Consequently, it is not surprising to find many reports of xenobiotic ketones that are i uced prefer-emi ly to a predominant stereoisomer. Often, ketone reduction yields dcohol metabolites that arc pharmacologically active. 

Suain differences in drug metabolism exist, particularly in inbred mice and rabbits. These differences apparently are caused by genetic variations in the amount of metabolizing enzyme present among the different strains. For example, in iitro studies indicate that cottontail rabbit liver microsomes metabolize hexobarbital about 10 times faster than New Zealand rabbit liver micro.somes. " Interindividual differences in dmg metabolism in humans are considered below. 

Dalvi, R.R., Nunn, V.A. Juskevich, J. (1987) Hepatic cytochrome P-450 dependent drug metabolizing activity in rats, rabbits and several food-producing species. Journal of Veterinary Pharmacology and Therapeutics, 10, 164-168. 

MJ Duane. Disposition kinetics and metabolism of nicotine-1 -N-oxide in rabbits. Drug Metab Dispos 19(3) 667-672, 1991. 

Because many drugs contain either chiral centers, prechiral centers, or both, interest in stereochemical substrate-enzyme interactions, the stereospecificity of biotransformations, and species (and strain) differences in these parameters is increasing. Since enzymes themselves contain chiral centers, differential interaction of R and S isomers of drugs with drug metabolizing enzymes is the rule rather than the exception. Beckett reported stereoselectivity in the N-dealkylation, deamination, and formation of the nitrone and secondary hydroxylamine metabolites (+) -and (-) - N-benzylamphetamine ( ) in rabbits. Stereoselectivity has also been observed in the dealkylation of d-, 1-, and d,1-fenfluramine (22), an anorexiogenic agent. 

There may be species differences in the induction of drug metabolism in extra-hepatic tissues. For example, treatment of rabbits with phenobarbital significantly increases the hydroxylation and N-demethylation of N-methylaniline and the microsomal protein and cytochrome P-4S0 content of liver and kidney microsomes, but not in lung and small intestine. However, treatment of rats with phenobarbital, 3,4-benzpyrene, or DDT does not significantly affect the levels of cytochrome P-4S0 or drug metabolism in kidney microsomes. 

Most species differences in drug metabolism, however, result from differences in the rates of enzymatic convosions. For example, a dose of 50 mg/kg of hexo-barbital produces anaesthesia in man or dog for over S hr but 100 mg/kg produces anaesthesia for 90 min in rats, for 49 min in rabbits and for only 12 min in mice. At the time of recovery from anaesthesia, the several animal spedes have remarkably similar brain barbiturate levels. Thus, the duration of action of hexo-barbital in several species is generally proportional to its biologic half life and inversely proportional to the rate of hexobarbital metabolism by enzymes in hepatic microsomes. 

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