Abstract:
Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET)
of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating
plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and
urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into
water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions
(which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conju-gation
with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model
provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibu-profen and propranolol) in
freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with
low metabolic competency may exhibit zero-order metabolic (pharmacoki-netic) profiles and thus high API toxicity, as in the case
of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African
Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism
(suggesting P450 Phase I enzyme system or Phase II glucuronida-tion deficiencies). While all aspects of ADMET are important in
toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a
central part of environmental risk assessment.
