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Mentions: A large scattering of data was observed in the ratio of AChE-inhibitory activity of patients’ plasma and the CPO concentration, whether or not patients had received pralidoxime. As expected, the inhibitory activity was on average higher in the group who did not receive pralidoxime. Fig. 4 shows the scatter of data from patients who were not administered pralidoxime (absence confirmed by HPLC). A hyperbola fitted by non-linear regression is shown (full line). The normal concentration of AChE in whole blood is about 15 nM [20,21], hence the concentration of AChE in the inhibition assay was about 11.3 nM. Using the inhibition rate constant of 6 × 106 M−1 min−1  allows a rough estimate of the inhibition progress, which was essentially complete after the 60 min incubation time. As shown in Fig. 4, in most cases AChE was inhibited to a less extent than predicted from the CPO concentration (dotted line). The ratio of inhibitory activity found/predicted in samples with and without PAM did not depend on the CPO concentration as shown in the semilogarithmic plot of Fig. 5. Linear regression analysis of the data indicated that the slopes were not significantly different from zero (p >0.2 and >0.5, respectively). These results pointed to competing side reactions of CPO during the incubation period.
Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF)
Bottom Line: 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 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.
Affiliation: Toxicological Department of the 2nd Medical Clinic, Technische Universität München, Ismaninger Str. 22, D-81664 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 72h. 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.
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