An interesting aspect is the way caffeine biotransformation reactions proceed in higher plants, the variability of caffeine catabolism again being dependent on species and to a greater extent, on the age of different tissues investigated. As an example, it was reported that in young tea leaves, theophylline is re-utilised for caffeine biosynthesis, while in aged leaves of Coffea arabica, it undergoes further metabolism resulting in 7-methylxanthine accumulation. Other species of Coffea have been proven to convert caffeine to methyluric acids. Obviously, these cases exemplify qualitative differences, as well as species- and age-dependence. A well-known quantitative example is that of species variation in hexobarbitone metabolism, affecting half-life and sleeping time.

Investigations have been made on man, dog, mice and the rat. The longest half-time was registered for man (~360 min). The sleeping time increased in the following order: mice, rats, dogs and man. The main conclusion of the experiment, apart from demonstrating that the oxidative metabolism of hexobarbitone is markedly influenced by species, was that the biotransformation is inversely related to the half-time and duration of action of the investigated drug, the highest metabolism being registered for mice and decreasing in the opposite order as for the sleeping time for example. A recent example refers to the variation in the metabolism of selegiline ((-)-form of deprenyl) in seven different species. From literature data, it is known that selegiline undergoes N-dealkylation, yielding several metabolites, namely N-desmethylselegiline, methamphetamine and amphetamine.

The investigations made during the study referred to, and performed on liver microsomes of different species, in addition to characterizing the potential metabolic variations, also proved the existence of another metabolite, the N-oxide. The rate and extent of formation of this metabolite was found to be markedly influenced by species, the highest rate of production occurring in dog and hamster, being much lower in humans, and zero in the rat.

 Another example of quantitative variation was revealed from experimental studies investigating the metabolic profile of a relatively novel diuretic. A comparative approach was adopted, aimed at demonstrating its metabolism in experimental animals and human liver microsomes. Increased rates of metabolism were observed in rats and monkeys, and six metabolites, designated RU1, RU2, RU3 and MU1, MU2, MU3 for the respective species, were identified in their urine. Quantitatively, only three of these were considered to be major metabolites in rat and monkey urine, namely RU3, RU1 and MU3 respectively, whereas in the dog, the unchanged drug was observed as the major urinary component. This indicated a net difference between the rat and the monkey, both displaying extensive biotransformation, and the dog, in which only little metabolism occurred.

 In contrast with dogs, humans showed similarities with rats, suggesting a common metabolic pathway. Six species have been investigated in connection with the psychoactive drug of abuse 4-bromo-2,5-dimethoxyphenethylamine (2C-B) (street names ‘Venus’, ‘Bromo’, ‘Erox’, ‘XTC’ or ‘Nexus’). Hepatocytes from human, monkey, dog, rabbit, rat and mouse were incubated with 2C-B in an attempt to identify the resulting metabolites and to monitor possible toxic effects.

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