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Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF) |
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| Authors: | Florian Eyer Nicholas A. Buckley Horst Thiermann Peter Eyer |
| Affiliation: | a Toxicological Department of the 2nd Medical Clinic, Technische Universität München, Ismaninger Str. 22, D-81664 Munich, Germany b South Asian Clinical Toxicology Research Collaboration, and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Australia c South Asian Clinical Toxicology Research Collaboration, and Professorial Medical Unit, University of NSW, Sydney, Australia d Scottish Poisons Information Bureau, Royal Infirmary, and Clinical Pharmacology Unit, University of Edinburgh, UK e Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany f Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig Maximilians University, Goethestr. 33, D-80336 Munich, Germany |
| Abstract: | Chlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, this presumed metabolite has escaped detection in human samples by conventional methods (HPLC, GC-MS, LC-MS) until now. A recently developed enzyme-based assay allowed the determination of CPO in the nanomolar range and was successfully employed to detect this metabolite. CPO and CPF were analysed in consecutive plasma samples of 74 patients with intentional CPF poisoning. A wide concentration range of CPO and CPF was observed and the ratio of CPO/CPF varied considerably between individuals and over time. The ratio increased during the course of poisoning from a mean of 0.005 in the first few hours after ingestion up to an apparent steady-state mean of 0.03 between 30 and 72 h. There was a hundred-fold variation in the ratio between samples and the interquartile range (between individuals) indicated over half the samples had a 5-fold or greater variation from the mean. The ratio was independent of the CPF concentration and the pralidoxime regimen. CPO was present in sufficient quantities to explain any observed acetylcholinesterase inhibitory activity. The effectiveness of pralidoxime in reactivating the inhibited acetylcholinesterase is strongly dependent on the CPO concentration. Differences in clinical outcomes and the response to antidotes in patients with acute poisoning may occur due to inter-individual variability in metabolism. |
| Keywords: | AChE, acetylcholinesterase (EC 3.1.1.7) BChE, butyrylcholinesterase (EC 3.1.1.8) CPF, chlorpyrifos CPO, chlorpyrifos oxon PON 1, paraoxonase 1 (EC 3.1.8.1) RBC, red blood cells |
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