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Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF).

Eyer F, Roberts DM, Buckley NA, Eddleston M, Thiermann H, Worek F, Eyer P - Biochem. Pharmacol. (2009)

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.

View Article: PubMed Central - PubMed

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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Ratio of CPO/CPF vs. time post-ingestion of CPF. Data are median values with their IQRs of 72 eligible patients from Table 1. For illustration a mono-exponential association function was fitted to the median values.
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fig2: Ratio of CPO/CPF vs. time post-ingestion of CPF. Data are median values with their IQRs of 72 eligible patients from Table 1. For illustration a mono-exponential association function was fitted to the median values.

Mentions: Formation of CPO occurred quite early after CPF ingestion. In one patient we detected significant amounts of CPO 70 min after CPF ingestion with BChE and AChE depressed to less than 2% and 10% of normal, respectively. Fig. 1 shows the time course of plasma CPF and CPO in a patient who was admitted some 5 h post-ingestion and received no pralidoxime. Here, maximal CPO concentration appeared after a delay of several hours. As expected, the ratio of CPO/CPF increased with time, starting with less than 0.005 in the period between 0 and 4 h after ingestion and approaching 0.03 on average in the period between 24 and 120 h. Table 1 shows the median plasma concentrations along with the interquartile ranges of CPF and CPO in 72 eligible patients (with and without pralidoxime treatment, no significant difference), where sufficient data were available to determine the CPO/CPF ratio at various time intervals post-ingestion. Fig. 2 shows the time course of the ratio of CPO/CPF and a mono-exponential association curve that was fitted to the median values, without implying a specific mechanism.


Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF).

Eyer F, Roberts DM, Buckley NA, Eddleston M, Thiermann H, Worek F, Eyer P - Biochem. Pharmacol. (2009)

Ratio of CPO/CPF vs. time post-ingestion of CPF. Data are median values with their IQRs of 72 eligible patients from Table 1. For illustration a mono-exponential association function was fitted to the median values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2714474&req=5

fig2: Ratio of CPO/CPF vs. time post-ingestion of CPF. Data are median values with their IQRs of 72 eligible patients from Table 1. For illustration a mono-exponential association function was fitted to the median values.
Mentions: Formation of CPO occurred quite early after CPF ingestion. In one patient we detected significant amounts of CPO 70 min after CPF ingestion with BChE and AChE depressed to less than 2% and 10% of normal, respectively. Fig. 1 shows the time course of plasma CPF and CPO in a patient who was admitted some 5 h post-ingestion and received no pralidoxime. Here, maximal CPO concentration appeared after a delay of several hours. As expected, the ratio of CPO/CPF increased with time, starting with less than 0.005 in the period between 0 and 4 h after ingestion and approaching 0.03 on average in the period between 24 and 120 h. Table 1 shows the median plasma concentrations along with the interquartile ranges of CPF and CPO in 72 eligible patients (with and without pralidoxime treatment, no significant difference), where sufficient data were available to determine the CPO/CPF ratio at various time intervals post-ingestion. Fig. 2 shows the time course of the ratio of CPO/CPF and a mono-exponential association curve that was fitted to the median values, without implying a specific mechanism.

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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus