An Factors that influence of species, sex, age, hormonal status and disease state on drug biotransformation forms the major part of these parameters collectively being referred to as ‘intrinsic factors’. Reported results of several recent studies of these factors are reviewed, with the aim of indicating their variable nature as well as their interdependence. Thus, for example, we will encounter cases where for certain drugs, there are only subtle differences in the biotransformation routes in different species, while for others, dramatically different pathways are adopted, leading to the formation of vastly different metabolic products. Interdependence of most of these factors is a natural expectation, given that the status of an individual’s metabolising activity and pathological status vary over a lifetime. Thus, for example, the effects of natural attrition of the metabolising activity in an aged patient and a specific disease state can interact in a way that results in a unique mode of metabolic clearance of a drug. One significant point emerges from the discussion, namely the variability in the outcomes of drug metabolism observed for different species.

This unpredictable element reminds us of the caution that should be exercised in extrapolating from animal studies to humans and the implications that this has in the evaluation of new drugs in the pharmaceutical industry. The final section of this chapter summarises the effects of external (environmental) factors on drug biotransformation, examples of which were encountered in earlier chapters. Continual introduction of new chemical substances into the environment through waste production and industrial activity remains a major international issue, necessitating inter alia on-going studies of their effects on human drug metabolism.

Drugs, as well as other xenobiotics are metabolise via various pathways, including phase I and phase II reactions, which involve participation of numerous enzyme systems. Therefore, it is reasonable to assume that there are many factors that can determine or influence along which pathway a particular drug will undergo biotransformation and the extent to which this will proceed. These factors are usually arbitrarily divided into internal and external factors, with nevertheless considerable interaction between them. Examples of species differences in drug biotransformation are numerous, continuously investigated, and encountered in both phases of biotransformation. An interesting observation is that they may involve the same route, but differ in the rate along that particular pathway (i.e. quantitatively different) or they may adopt different pathways (i.e. differing qualitatively).

It should be noted as well that there is not always a direct relationship between metabolism, half-life and action of a drug. Selected examples an interesting quantitative species difference in phase I metabolism is known for caffeine, both in terms of total metabolism and metabolite production. Thus, the total metabolism is highest in humans, decreasing in the order - monkey, rat and rabbit. While there are no significant differences in the formation of theobromine, marked differences have been recorded for the other two metabolites, paraxanthine and theophylline, with paraxanthine formation highest in humans and lowest in monkey, whereas the reverse obtains for theophylline.

Best Regards,
Nancy Ella
Editor-In-Charge
Drug Designing: Open Access