Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat

Busby-Hjerpe, Andrea L.; Campbell, James A.; Smith, Jordan N.; Lee, Sookwang; Poet, Torka S.; Barr, Dana Boyd; Timchalk, Charles

doi:10.1016/j.tox.2009.11.022

Cited by 22 publications

(11 citation statements)

References 56 publications

(72 reference statements)

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“…Such ancillary information do not satisfy the criteria of exposure to a specific pesticide, but rather indicate that the OPs were used in some ill-defined proximity and timing to people. While co-occurrence of specific OP metabolites with DAPs may help to bolster the value of DAP measurements, the specific OP metabolites are also bioavailable (Timchalk et al, 2007;Busby-Hjerpe et al, 2010;and Chen et al, 2012b), and co-exist at higher concentrations than the parent OP in environmental media (Morgan et al, 2005;Chen et al, 2012a). Thus, DAPs used as a surrogate for residential OP exposure are extremely biased by their high oral bioavailability and ubiquitous presence in food at concentrations several-fold greater than parent OPs.…”

Section: Commentarymentioning

confidence: 99%

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Krieger

Chen

Ginevan³

et al. 2012

Regulatory Toxicology and Pharmacology

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Section: Commentarymentioning

confidence: 99%

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Krieger

Chen

Ginevan³

et al. 2012

Regulatory Toxicology and Pharmacology

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“…Pharmacokinetic studies of CPF in rat models have primarily been performed in animals administered a single bolus dose (Busby-Hjerpe et al 2010; Marty et al 2007; Smith et al 2009; Timchalk et al 2007; Timchalk et al 2002), with the exception of one study that investigated the pharmacokinetics of CPF in neonatal rats (Marty et al 2007) and another that studied combined exposure to nicotine and CPF (Lee et al 2010). Since occupational exposures often consist of repeated daily exposures (Farahat et al 2011; Farahat et al 2010; Farahat et al 2003), there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF and other OPs under exposure conditions which more accurately reflect real world human exposures.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos

et al. 2011

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Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. Several pharmacokinetic and pharmacodynamic studies have been conducted in rats in which CPF was administered as a single bolus dose. However, there is limited data regarding the pharmacokinetics and pharmacodynamics following daily exposure. Since occupational exposures often consist of repeated, daily exposures, there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF under exposure conditions which more accurately reflect real world human exposures. In this study, the pharmacokinetics and pharmacodynamics of CPF were assessed in male Long Evans rats exposed daily to CPF (0, 3 or 10mg/kg/day, s.c. in peanut oil) over a ten day study period. Throughout the study, multiple pharmacokinetic (urinary TCPy levels and tissue CPF and metabolite levels) and pharmacodynamic (blood and brain AChE activity) determinants were measured. Average blood AChE activity on day ten was 54 and 33 percent of baseline among animals in the 3 and 10mg/kg/day CPF treatment groups, respectively, while average brain AChE activity was 67 and 28 percent of baseline. Comparable dose-response relationships between brain AChE inhibition and blood AChE inhibition, suggests that blood AChE activity is a valid biomarker of brain AChE activity. The pharmacokinetic and pharmacodynamic measures collected in this study were also used to optimize a rat physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for multiple s.c. exposures to CPF based on a previously published rat PBPK/PD model for CPF following a single bolus injection. This optimized model will be useful for determining pharmacokinetic and pharmacodynamic responses over a wide range of doses and durations of exposure, which will improve extrapolation of results between rats and humans.

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“…It is known that hepatic CYP450s play an integral role in phase I metabolism of environmental chemicals and drugs (Ackley et al, 2004; Wu and McKown, 2004; Yan et al, 2002). While it has been shown that cytochrome P450s, CYPs, participate in the detoxification of OPs via the hydrolysis of the OP phospho ester bond to yield DAPs, it has also been demonstrated that CYP-mediated bioactivation of OPs to oxons is a major contributor to overall OP toxicity (Poet et al, 2003; Buratti et al, 2003; Buratti et al, 2005; Busby-Hjerpe et al, 2010; Bharate et al, 2010; Casida and Quistad, 2004). In light of the importance of CYP-mediated bioactivation to the toxicity of OPs, it was hypothesized that they may play an equally important role in DAP metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been demonstrated that the ethylated DAP hydrolysis products of chlorpyrifos are excreted in the urine of rats orally dosed with O,O -diethylphosphate, DEP, and O,O -diethylthiophosphate, DETP (Shafik et al, 1971; Timchalk et al, 2007; Busby-Hjerpe et al, 2010). Additionally, the afore-mentioned ethyl DAP toxicokinetic studies demonstrated that exposure to equal molar levels of ethylated DAPs and chlorpyrifos consistently resulted in higher urinary ethyl DAP excretion rates and cumulative urine levels in rats receiving oral doses of ethyl DAPs (Timchalk et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Organophosphorus pesticide degradation productin vitrometabolic stability and time-course uptake and elimination in rats following oral and intravenous dosing

Forsberg

Rodriguez-Proteau

et al. 2011

Xenobiotica

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Levels of urinary dialkylphosphates (DAPs) are currently used as a biomarker of human exposure to organophosphorus insecticides (OPs). It is known that OPs degrade on food commodities to DAPs at levels that approach or exceed those of the parent OP. However, little has been reported on the extent of DAP absorption, distribution, metabolism and excretion.The metabolic stability of O,O-dimethylphosphate (DMP) was assessed using pooled human and rat hepatic microsomes. Time-course samples were collected over two hours and analyzed by LC-MS/MS. It was found that DMP was not metabolized by rat or pooled human hepatic microsomes.Male Sprague-Dawley rats were administered DMP at 20 mg kg−1 via oral gavage and I.V. injection. Time-course plasma and urine samples were collected and analyzed by LC-MS/MS. DMP oral bioavailability was found to be 107 ± 39 % and the amount of orally administered dose recovered in the urine was 30 ± 9.9 % by 48 hrs.The in vitro metabolic stability, high bioavailability and extent of DMP urinary excretion following oral exposure in a rat model suggests that measurement of DMP as a biomarker of OP insecticide exposure may lead to overestimation of human exposure.

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Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat

Cited by 22 publications

References 56 publications

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos

Organophosphorus pesticide degradation productin vitrometabolic stability and time-course uptake and elimination in rats following oral and intravenous dosing

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