Drug biotransformation animal species

The biotransformation of certain drugs may differ in males and females. Such sex differences are fairly common in the rat, which is probably the most widely utilized laboratory animal in drug safety evaluation, but have been infrequently reported for humans or even for other laboratory animal species. When encountered, these sex differences appear to arise as a result of the regulation of drug biotransformation by hormones such as growth hormone. 

The biotransformation of many drugs is often slower in humans than in the laboratory animal species used in drug development and safety evaluation. Lower activities of the respective enzyme systems may be the cause, and indeed the rates of drug biotransformation and the bodyweights of animal species appear to be correlated to some extent. 

Species variations in the half-life of drugs that are eliminated by renal excretion is less pronounced than for lipid-soluble drugs that undergo extensive hepatic biotransformation. The half-life of gentamicin, which is eliminated solely by glomerular filtration, is 0.5-1 h in laboratory animals, 1.25-2.5 h in domestic animals. 

A typical example of an effective bioprecursor prodrug is given by the anti-inflammatory drug sulindac. Sulindac, di-5-fluoro-2-methyl-l-[p-(methylsulfinyl) benzylidene] indene-3 acetic acid is a non-steroidal anti-inflammatory agent having a broad spectrum of activity in animal models and in man. The two quantitatively significant biotransformations undergone by sulindac in laboratory species and... 

Several research groups have demonstrated that species differences in the biotransformation of drugs with diverse but known in vivo metabolite patterns, could be reproduced with hepatocytes. Hepatocytes from diverse species like rats, rabbits, dogs, monkeys and man have been used to study the biotransformation of tolbutamide 37), amphetamine 38), ketitofen 39) and diazepam 40). These and other comparative studies again demonstrate that in general extrapolation of data obtained with cellular fractions, hepatocytes or intact animals from one species to another species is not possible, and stresses the need for the use of target-animals for risk-assessment purposes. 

The problems posed by species differences for the development and screening of new drugs are considerable. Knowledge of the mechanism of biotransformation of a new chemical agent in animals is, however, fundamental to its safety evaluation. 

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