The role of pharmacokinetics and metabolism in species sensitivity to neurotoxic agents.
Attempts have been made to review the role of pharmacokinetics and metabolism in species and age sensitivity as well as the development of various toxic conditions of some neurotoxic chemicals. The route of administration may play a prominent role in the development of various toxic effects of some organophosphorus compounds such as DEF. Such variation was attributed to the differential metabolism which was found to be highly dependent on the route of administration. It is obvious from the data presented here that animals that are sensitive to OPIDN are less active in the metabolism and elimination of the neurotoxic chemical and/or its metabolite(s). So, a compound may stay for a longer period in the body of the sensitive animals resulting in greater accessibility of target tissues to the deleterious effects of the neurotoxic compounds. However, many of these neurotoxic chemicals require metabolic activation to exert their effect. While the insensitive species may convert the compound to its active metabolite faster than that of the insensitive species, this is circumvented by the far greater capability of the insensitive animals to metabolize the active metabolite and/or the parent compound to less toxic, more polar, excretable metabolites. However, it must be stressed that these studies are far from complete, and caution should be exercised in interpreting and correlating many of these results. It is difficult, and sometimes misleading to compare data from various studies due to differences in dosage, the number of animals used, route of administration, experimental protocols, etc. With respect to hexacarbons, species sensitivity is obvious, but not as extensively investigated as OPIDN. To our knowledge, no studies are available addressing species difference in pharmacokinetics and metabolism of these chemicals. The data presented in this review suggest that metabolism and pharmacokinetics may play an important role in the development of OPIDN. However, this does not rule out the influence of other factors such as target sensitivity. This necessitates further qualitative and quantitative metabolic studies which are carefully planned to address these issues.
M B
MB
Abou-Donia
A A
AA
Nomeir
D000375:Aging; D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006838:Hydrocarbons / Q000633:toxicity; D007700:Kinetics; D010773:Leptophos / Q000633:toxicity; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects*; D063086:Organothiophosphates / Q000633:toxicity; D004849:Phenylphosphonothioic Acid, 2-Ethyl 2-(4-Nitrophenyl) Ester / Q000633:toxicity; D012967:Sodium Dodecyl Sulfate; D013045:Species Specificity; D013116:Spinal Cord / Q000201:enzymology; D014317:Tritolyl Phosphates / Q000378:metabolism
D000814:Aniline Compounds; D002800:Cholinesterase Inhibitors; D006838:Hydrocarbons; D063086:Organothiophosphates; D014317:Tritolyl Phosphates; C009525:tributyl thiophosphate; D004849:Phenylphosphonothioic Acid, 2-Ethyl 2-(4-Nitrophenyl) Ester; C011716:4-chloro-N-methylaniline; D012967:Sodium Dodecyl Sulfate; D003577:Cytochrome P-450 Enzyme System; D010773:Leptophos; D006899:Mixed Function Oxygenases; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; C025541:tri-o-cresyl phosphate