ToxSci Advance Access originally published online on December 3, 2007
Toxicological Sciences 2008 101(2):197-205; doi:10.1093/toxsci/kfm277
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Toxicokinetics and Tissue Distribution of Deltamethrin in Adult Sprague–Dawley Rats
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602
3 To whom correspondence should be addressed at the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30605. Fax: (706) 542-5358. E-mail: bruckner{at}rx.uga.edu.
Received October 19, 2007; accepted October 30, 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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The objectives of this study were twofold: (1) to characterize the toxicokinetics and dose-dependent systemic/tissue distribution of deltamethrin (DLM) over a range of doses in adult Sprague–Dawley (S–D) rats; (2) to provide comprehensive time course blood and tissue data for development of a physiologically based toxicokinetic (PBTK) model for DLM. DLM is one of the more neurotoxic members of a relatively new and commonly used class of insecticides, the pyrethroids. Despite widespread exposure of the general population to pyrethroids, there is little basic toxicokinetic (TK) data to use in health risk assessments or in development of PBTK models. Male S–D rats were dosed orally with 0.4, 2, or 10 mg DLM/kg dissolved in glycerol formal (GF). Another group received 2 mg/kg iv. Serial blood and tissue samples were taken at sacrifice and analyzed by high-performance liquid chromatography for their DLM content, in order to obtain comprehensive time course data sets for estimation of classical TK, as well as PBTK parameters (e.g., tissues:blood partition coefficients). Gastrointestinal (GI) absorption of DLM was rapid but incomplete. Bioavailability was just 18%. Some 83% of DLM in blood was present in the plasma. Just 0.1–0.3% of systemically absorbed doses reached the brain, the target organ of the bioactive parent compound. Fat, skin and surprisingly, skeletal muscle, accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Tissue distribution was dose dependent, though generally not proportional to dose. Clearance was dose independent in this dosage range. The time-profiles were used by A. Mirfazaelian et al. (2006
, Toxicol. Sci. 93, 432–442) to construct and adjust a PBTK model. Much remains to be learned about physiological/biochemical processes and barriers that govern the GI absorption, transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans. Key Words: pyrethroid; deltamethrin; toxicokinetics; PBTK modeling; bioavailability; tissue distribution.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Pyrethroids, synthetic derivatives of pyrethrins, have enjoyed increasing use as wide-spectrum insecticides. Casida and Quistad (1998)
reported that pyrethroids accounted for 23% of the worldwide insecticide market in 1995. Their use in the United States has increased substantially since 1998, due to the Environmental Protection Agency's (EPA's) concern about possible adverse effects of organophosphates on neurodevelopment in children. The widespread use of pyrethroids in forestry, agriculture, and the home has resulted in their frequent detection in humans (Berkowitz et al., 2003; Heudorf et al., 2004; Whyatt et al., 2002).
Traditionally, pyrethroids are divided into two classes based on their structure and toxic effects. Type I compounds do not contain a cyano group, but Type II compounds do. Type I compounds can cause tremors and skin parathesias. Major signs of acute poisoning by Type II compounds include salivation, hyperexcitability, tremors, and choreoathetosis (Soderlund et al., 2002; Wolansky et al., 2006). Deltamethrin (DLM), a commonly used Type II pyrethroid, was selected for the current investigation because it, unlike most other commercial pyrethroids, is available as a single isomer and is one of the most potent neurotoxicants of this class of chemicals (Choi and Soderlund, 2006; Wolansky et al., 2006). The parent compound is the proximate toxicant, as demonstrated by rapid manifestation of neurotoxicity upon intracerebral injection of mice (Lawrence and Casida, 1982); potentiation of toxicity by inhibitors of its metabolism (Casida et al., 1983; Soderlund and Casida, 1977); and correlation of brain DLM levels with clinical signs in rats (Rickard and Brodie, 1985). DLM and other pyrethroids are believed to act primarily by binding to voltage-dependent sodium channels in neurons, thereby prolonging their opening (Choi and Soderlund, 2006; Wang et al., 2001).
Toxicokinetic (TK) data for DLM and most other pyrethroids are very limited and in some cases contradictory (Sudakin, 2006). Anadón et al. have reported some of the most comprehensive TK studies of permethrin (1991), DLM (1996), and lambda-cyanohalothrin (2006). They delineated time courses of the parent compounds in plasma and different regions of the brain after administration of a toxic dose to rats. Pyrethroid levels in most brain areas were substantially higher than plasma levels. Gray and Rickard (1982) and Rickard and Brodie (1985), in contrast, measured markedly higher 14C-DLM concentrations in rat plasma than in brain. Common deficiencies of studies from which the DLM TK database (ATSDR, 2003) were obtained include: use of highly toxic doses; administration of a single dosage level, sometimes by an irrelevant exposure route; lack of DLM concentration data for key organs and tissues; and failure to sample long enough to delineate elimination profiles and standard TK indices.
The U.S. EPA and other regulatory agencies are currently evaluating health risks of pyrethroids. TK studies are playing an increasingly important role in reducing uncertainties inherent in risk assessments. Chemical toxicity is a dynamic process, in which the degree and duration of adverse effect are dependent on the amount of toxic moiety reaching and remaining at the site of action. The target tissue dose and effects are dependent upon the net effect of absorption, tissue deposition, metabolism, and elimination. Gaining an understanding of these processes and learning how they differ with exposure route, dose, and species will greatly reduce the number of unsubstantiated assumptions that must be made in risk assessments of pyrethroids in humans. TK data can be used to construct physiologically based TK (PBTK) models to predict internal dosimetry of these pesticides for different exposure scenarios with reasonable scientific certainty.
An objective of this study was to conduct a comprehensive investigation of the TK of DLM over a range of oral doses in the adult rat. This study was part of a research project designed to elucidate the TK of pyrethroids in immature and adult animals, and to utilize the data to develop and validate PBTK models for use in risk assessments for different age groups. In light of DLM's high lipophilicity, experiments were designed to test the following hypotheses: gastrointestinal (GI) absorption is rapid and complete; brain, skin, and fat accumulate and retain relatively high levels of parent compound for a prolonged period; DLM partitions into erythrocyte (rbc) membranes for transport in the blood; and modest levels in lean tissues are eliminated relatively quickly.
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MATERIALS AND METHODS |
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Chemicals.
(S)-
-cyano-3-phenoxybenzyl-(1R,cis)-2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-1-carboxylate (DLM) (98.8%) was kindly provided by Bayer CropScience AG (Monheim, Germany). DLM's chemical structure is shown in Figure 1. Acetonitrile (high-performance liquid chromatography [HPLC] grade) and glycerol formal (GF) were purchased from Sigma-Aldrich (St Louis, MO). Methanol, sulfuric acid, and deionized water were obtained from J.T. Baker (Phillipsberg, NJ). All other chemicals used were of the highest grade commercially available.
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Animals.
Male adult (
90 day old) Sprague–Dawley (S–D) rats were obtained from Charles River Breeding Laboratories (Raleigh, NC). The protocol for this study was approved by the University of Georgia Animal Care and Use Committee. The animals were housed in pairs in polycarbonate cages in an Association for Assessment and Accreditation of Laboratory Animal Care-approved animal facility with a 12-h light/dark cycle (light 6:00 A.M.–6:00 P.M.) at 22 ± 2°C and 55 ± 5% relative humidity. Food (5001 Rodent Diet, PMI Nutrition International) (Brentwood, MO) and tap water were provided ad libitum during an acclimation period of at least 10 days.
Plasma oral and IV experiments.
Fasted male S–D rats of 330 ± 19 g (x ± SD) were administered 2 mg DLM/kg in GF orally (2 ml/kg) or by iv injection (0.2 ml/kg) into a caudal tail vein. Groups of 4 (iv) or 5 (po) animals were sacrificed by cervical dislocation at selected time points for up to 36 h after dosing. The 2 mg/kg po group data were obtained in the Tissue Disposition Experiment. Blood samples were taken immediately following sacrifice by cardiac puncture. Plasma was obtained from each sample for DLM analysis by centrifuging and processing it as subsequently described in the Extraction and Analysis subsection. Standard TK parameters were calculated from the oral and iv time course data as described in the TK Data and Statistical Analyses subsection.
Tissue disposition experiment.
The aim of this experiment was to delineate plasma and tissue uptake and elimination time-profiles for a series of DLM doses. Three oral dosages were selected: 0.4, 2.0, and 10.0 mg DLM/kg. Groups of five rats were used at each dose level. It was not possible to utilize a dose lower than 0.4 mg/kg due to the limit of quantitation of our assay. It was not advisable to exceed 10 mg/kg, in order to avoid marked neurotoxicity. This dosage produced transient salivation and tremors. Rats of 388 ± 56 g (x ± SD) were provided water ad libitum but fasted for 12 h prior to treatment, in order to avoid intersubject variability in GI absorption due to varying food intake. Groups of rats were gavaged with each of the three dosages in GF (total volume = 2 ml/kg). Access to food was provided 3 h after dosing. Rats were euthanized with CO2 after 0.5, 1, 2, 6, 12, 24, 48, 72, and 96 h, as well as 2 and 3 weeks postdosing. Blood samples were drawn from the inferior vena cava and collected in heparinized tubes. Plasma and red blood cells (rbcs) were obtained by centrifuging the 150 µl of blood samples at 3,850 g for 5 min at 4°C in a microcentrifuge (Microfuge 22R Beckman Coulter) (Fullerton, CA). The whole brain, left kidney, ventral skin (hair removed), a part of the liver's median lobe, and portions of perirenal fat and thigh muscle were then excised and stored at –80°C until analysis. Whole blood, plasma, rbc, and tissues were analyzed for DLM as described below.
DLM extraction and analysis.
The DLM content of the biological samples was quantified by the procedure of Kim et al. (2006). Sixty-five microliters of whole blood, plasma, or rbc were transferred to microcentrifuge tubes containing 130 µl of acetonitrile. The tubes were vortexed (Mini Vortexer, VWR) (West Chester, PA) for 30 s, and then centrifuged for 5 min in the microcentrifuge at 16,000 g. The clear supernatant (50 µl) was subsequently injected into a HPLC as described below. Each tissue was homogenized in four volumes of 50% acetonitrile in distilled water (vol:vol) with a Tekmar Tissumizer (Cincinnati, OH). Sixty-five microliters of the tissue homogenates were transferred to microcentrifuge tubes containing 130 µl of acetonitrile. The tubes were vigorously agitated on the vortex mixer for 30 s, and subsequently centrifuged for 5 min at 16,000 g. An aliquot of the clear supernatant (50 µl) was then injected into a HPLC.
The HPLC unit was a Shimadzu (Canby, OR) equipped with a LC-10AT pump, a DGU-14A degasser, a SIL-HT autosampler, an SPD-10AV detector, and an EZStart 7.2 SP1 Rev B computer. The analytical column was an Ultrasorb 5 ODS 20 (250 mm x 4.6 mm, 5 µm particle) (Phenomenex, Torrance, CA), and the guard column was a Phenomenex Fusion RP (4 mm x 3 mm). The mobile phase was 80% acetonitrile and 20% HPLC water-diluted sulfuric acid (1%) (vol:vol). The flow rate was 1 ml/min. The eluate was monitored at 230 nm. DLM eluted at 14.5 min under these conditions. A series of calibration curves (0.01–2.5 µg/ml) was prepared in respective tissue matrices and run each day samples were analyzed. The absolute recoveries ranged from 93 to 108% for plasma and tissues. The method was linear over the range of 0.01–20 µg/ml. The inter- and intraday variations were in the range of 0.7–15.2% relative standard deviation. The limits of detection (LOD) and quantitation (LOQ) for the method were 0.01 and 0.05 µg DLM/ml, respectively, for the biological samples analyzed (Kim et al., 2006). DLM concentrations in plasma, blood, and rbc were directly measured in the 10 mg DLM/kg group 2 and 6 h postdosing. From this pilot experiment, it was established that rbc DLM levels were only 7% of blood levels. Therefore, rbc DLM levels at each time-point for all three dosage groups were calculated using the formula: DLM levelrbc = 0.071 x DLM levelblood.
TK data analyses.
Means and SEs were calculated with Microsoft Excel 2003 (Microsoft Co., Redmond, WA). TK parameters, including area under the blood DLM concentration versus time curve (AUC0
), volume of distribution (Vd), clearance (CL), and terminal elimination half-life (t
), were calculated using WinNonlin (ver. 4.1) noncompartmental model analysis by Scientific Consulting, Inc. (Cary, NC). The maximum blood concentration (Cmax) and time of maximum blood concentration after dosing (Tmax) were observed values. Bioavailability (F) was calculated using the equation: F = AUCoral/AUCiv. Partition coefficients (PCs) were calculated using the equation AUCtissue/AUCplasma or AUCBlood.
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RESULTS |
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Plasma TK
Plasma DLM time courses in rats administered 2 mg DLM/kg by gavage or iv injection are pictured in Figure 2. The iv animals experienced salivation and tremors that persisted for 6–12 h. It is evident that DLM is very rapidly distributed systemically following iv injection. In contrast, its systemic elimination is relatively slow, as reflected by a t
of 13.3 h (Table 1). DLM administered orally in GF was quickly absorbed (Tmax = 1 h), distributed, and eliminated at a rate similar to that following its iv injection. Despite its relatively rapid GI absorption and distribution, the bioavailability of DLM was only 18%. Vd, t, and CL did not vary significantly with route of administration (Table 1).
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Blood:Plasma Ratio
The tissue disposition experiment revealed that DLM is transported in the bloodstream largely in the plasma. Plasma, whole blood, and rbc DLM concentrations are contrasted 2, 6, and 12 h after adult S–D rats received 10 mg DLM/kg po (Fig. 3). It is evident that plasma levels far exceed rbc levels. Blood levels are lower than plasma levels as a result of blood's larger volume. Plasma/blood ratios do not change substantially over time. Mean plasma/blood ratios were also calculated by averaging the plasma/blood ratios for each sampling time from 1 to 48 h for each animal given the 2 and 10 mg/kg po doses (data not shown). The mean plasma/blood ratios for the 2 and 10 mg/kg groups were 0.83 ± 0.06 and 0.82 ± 0.5, respectively (x ± SE, n = 30). Thus,
83% of DLM in blood was present in the plasma. DLM levels 2 and 6 h after 0.4 mg/kg were close to the LOQ. They were below the LOD thereafter, so blood and plasma ratios were not calculated for this dosage.
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Dose Dependence of Tissue Disposition
Plasma and tissue DLM concentration-versus-time curves in orally dosed rats are shown in Figures 4 and 5. The plasma and tissue profiles clearly show dose–response relationships. Unfortunately, the parent compound was not detectable after 6 h in any samples from rats given 0.4 mg/kg. Therefore, it was not feasible to estimate accurate TK parameters for this lowest dose. DLM was measurable for up to 6, 24, and 48 h in the plasma and brain of the 0.4, 2, and 10 mg/kg groups, respectively (Figs. 4A and 4C). Visual inspection revealed that the plasma, liver, and kidney profiles resembled one another (Figs. 4A, 5A, and 5D
), but that brain concentrations (Fig. 4C) were substantially lower at each dosage. Fat concentrations (Fig. 4D), in contrast, were initially lower than plasma or blood levels, but subsequently markedly exceeded them and remained elevated for a much longer time. The time course of DLM in skin (Fig. 5B) resembled that in fat, although skin levels were initially lower. Muscle DLM concentrations were even lower during the uptake and distribution phases, but this tissue constituted 40% of total body weight, and elimination from it was unexpectedly slow (Fig. 5C).
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It was possible to assess the dose and tissue dependency of a number of DLM TK indices for the 2 and 10 mg/kg groups (Table 2). GI absorption and deposition of DLM in well-perfused organs (brain, liver, and kidney) were quite rapid, as manifest by Tmax values of 1 or 2 h for all three dosage-levels (Table 2). In most instances the 1- and 2-h DLM concentrations differed little from one another in both the 2 and 10 mg/kg groups. The poorly perfused, lipoidal tissues (i.e., fat and skin) exhibited the longest Tmax values (i.e., 6 and 12 h, respectively) (Table 2). The Tmax generally did not vary with dose. Inspection of the inset in Figure 5C revealed that the 2-, 6-, and 12-h muscle levels differed little from one another, as was the case for the 6-, 12-, and 24-h fat and skin levels (Figs. 4D and 5B insets). Cmax values were dose-dependent, but did not increase in direct proportion to dose. The increases in Cmax from 2 to 10 mg/kg were only
2- to 3-fold, with the exception of the brain and kidney, which were 4.5- and 3.5-fold, respectively. Increases in AUCs in this dosage range were more nearly proportional to dose in some instances (e.g., for plasma, fat, liver, and kidney) (Table 2). The fat AUC values far exceeded those of plasma and other tissues. DLM content in the skin over time was relatively high, followed by muscle.
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Relative Tissue DLM Content
Total DLM concentrations of the blood, plasma, and each tissue, analyzed 2 and 12 h after oral administration of 0.4, 2, and 10 mg DLM/kg, are listed in Table 3. Brain DLM burdens, even at the Tmax (2 h), are very low and account for only 0.1–0.3% of the body burden at 2 and 12 h, respectively. Conversely, the animals' adipose tissue and skin contain large amounts of the highly lipophilic insecticide. Concentrations are modest at 2 h, but increase significantly by 12 h, when levels in most other tissues have diminished substantially. The 2- and 12-h concentrations in skin are lower than those in fat (Table 3). This is counterbalanced by the skin's relatively large volume, resulting in comparable burdens and % body burdens for skin and fat 12 h after dosing (Table 3). Skeletal muscle's large volume is responsible for the tissue's sizable DLM content at 12 h, despite its modest DLM concentrations. Some 97% of the amount of DLM remaining in monitored tissues 12 h after administration of 2 and 10 mg/kg was present in the fat, muscle, and skin. Tissue DLM burdens were dose dependent, though the increases were not directly proportional to dose.
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Partition Coefficients
Partition coefficients (PCs) are presented as AUCtissue/AUCplasma and AUCtissue/AUCBlood in Table 2. Both tissue: plasma and tissue:blood PCs are presented. The tissue:blood values are larger, because blood DLM concentrations are lower than plasma concentrations (Fig. 3). PCs are essential input parameters for PBTK models. The PCs do not vary appreciably with DLM dose, with the exception of
2-fold higher muscle and skin values in the 10 than in the 2 mg/kg group. As expected, adipose tissue exhibits the highest PCs, followed in turn by skin and skeletal muscle. The PCs for brain are the lowest of all the biological specimens.
Tissue and Systemic Elimination
The terminal elimination half-lives varied substantially among the different organs and plasma/blood (Table 2). The brain, kidney, and plasma/blood exhibited the shortest t values. Plasma levels diminished somewhat more rapidly than whole brain levels, resulting in a progressive decline in plasma:brain AUC ratios (Fig. 6). The t values for liver were longer than those for plasma and brain, though the liver is the major site of DLM metabolism (Anand et al., 2006). DLM was most slowly eliminated from fat and skin, the most lipophilic tissues evaluated. Unexpectedly, elimination from skeletal muscle was equally slow. The rate of decrease in DLM concentrations in plasma and most tissues did not appear to be dose dependent from 2 to 10 mg/kg. Half-life values were comparable in each instance, with the exception of that for the skin.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Relatively little is known about the TK of DLM or other synthetic pyrethroids in humans and other mammals, despite frequent exposures of the populace to this relatively new class of insecticides. The time course data and TK parameter estimates presented here provide a comprehensive overview of the systemic uptake, disposition, and elimination of iv and oral DLM in adult rats. A key contribution of the work to risk assessment of DLM is information on the relationships among administered dose, internal dose (i.e., blood/plasma levels), and target organ dose (i.e., brain Cmax and AUC).
DLM appeared to be rapidly, but incompletely absorbed from the GI tract of fasted adult rats. Peak blood levels were manifest within 1–2 h, but bioavailability was only 18%. DLM is completely dissolved and rapidly absorbed when given orally to rats in GF (Kim et al., 2007). Interestingly, Anadón et al. (1996) reported a Tmax of 1.83 h and a bioavailability of 14.4% in fasted rats gavaged with 26 mg DLM/kg in sesame oil. It might be anticipated that the oil would act as a reservoir in the gut to delay the absorption of lipophilic chemicals (Kim et al., 1990). Digestible oils, however, have been shown to serve as carriers for highly lipophilic compounds such as dioxins and hexachlorobenzene into the lacteals (Lakshmanan et al., 1986; Roth et al., 1993), thereby bypassing first-pass hepatic metabolism. This may account for the comparable Tmax and F values we and Anadón et al. (1996) observed for DLM.
DLM was apparently not well absorbed from the GI tract, contrary to what we hypothesized. Bioavailability has also been reported to be low for other highly lipid-soluble chemicals including dioxin (Wang et al., 1997), benzo[a]pyrene (Foth et al., 1988), and other polyaromatic hydrocarbons (PAHs) (Roth et al., 1993). Tanabe et al. (1981) observed that the efficiency of oral absorption of PCB isomers diminished with increasing chlorine content (i.e., increasing lipophilicity). The basis for the low oral bioavailability is not known. In recent experiments, we found 40% of a single 10 mg DLM/kg oral dose was eliminated in the feces of rats (data not shown). DLM was not detectable in feces following its iv injection, suggesting that the chemical does not reenter the GI lumen by biliary excretion or by passive diffusion from mesenteric blood. P-glycoprotein (P-gp) is located on the GI luminal brush border membrane (Brady et al., 2002; Zhang and Benet, 2001) and may diminish DLM absorption in rats by acting as an efflux transporter. There has apparently been no evidence reported to date that DLM or other pyrethroids are P-gp substrates.
Efficient first-pass hepatic metabolism could contribute to DLM's low bioavailability. The hepatic extraction ratio would be anticipated to be quite low, however, judging from DLM's limited CL and the moderate rate of portal vein blood flow in rats. DLM has been shown to be primarily metabolized in vitro by adult rat hepatic microsomal CYP1A1 and 1A2, as well as by hepatic and plasma CaEs (Anand et al., 2006). Intrinsic CL was higher by the liver than by plasma. Godin et al. (2006) recently reported that DLM was metabolized primarily by oxidation in rat liver microsomes, but that hydrolysis predominated in human liver microsomes. Ross et al. (2006) found that CaEs in hepatic microsomes from mice, rats, and humans hydrolyzed cis- and trans-permethrin at similar rates in each species.
Relatively little DLM was found to be associated with rbc, in contrast to one of our proposed hypotheses. Measurements revealed that 83% of DLM was present in the plasma 2, 6, and 12 h after rats received 10 mg DLM/kg po. It has not been established whether DLM binds to plasma proteins. Halogenated biphenyls are thought to partition into hydrophobic regions of plasma proteins rather than bind to specific sites (Matthews et al., 1984). Low and high density lipoproteins are the major plasma acceptors of PAHs and halogenated aliphatics. A relatively low proportion of most PAHs are associated with rbc membranes, as was the case for DLM.
We had theorized that DLM would accumulate in the brain, due to its relatively high blood flow and lipid content. Based upon the brain DLM Cmax of 0.18 µg/g at the Tmax (2 h) and an assumed brain weight of 2 g in a 388 g rat, we calculated that only 0.29% of the total body burden of rats given 10 mg/kg was present in the whole brain (Table 3). This phenomenon remains to be explained. The brain's largely phospholipid composition may be a factor in limited partitioning of highly lipophilic DLM. DLM readily exits the blood and enters the other organs and tissues studied, but may be limited by the blood–brain barrier. Substantial amounts of P-gp in the blood–brain (Brady et al., 2002) and cerebrospinal (Choudhuri et al., 2003) barriers may serve as effective efflux transporters. This supposition is supported by DLM's relatively short t in brain (Table 2), though pyrethroids are yet to be shown to be P-gp substrates. Brain lipids of Inuit people from Greenland contain lower concentrations of 11 organochlorines and 14 PCB congeners than do lipid extracts from their liver, omental fat, and subcutaneous fat (Dewailly et al., 1999).
It was not anticipated that whole brain DLM Cmax and AUC0 values would be lower than blood/plasma or lean tissues values. Anadón et al. (1996) described markedly higher DLM concentrations in five of six brain regions than in plasma of orally dosed rats. Gray and Rickard (1982) and Rickard and Brodie (1985), however, had previously reported brain DLM levels to be much lower than blood levels. The reasons for this discrepancy are not clear, though our blood Cmax values at 10 mg/kg were 10-fold higher than those of Anadón et al. at 26 mg/kg. The profound neurotoxicity observed by Anadón et al. may have had pronounced effects on DLM's TK.
Adipose tissue, skin, and skeletal muscle were shown to be the major depots for DLM. Tmax values were relatively long for these poorly perfused tissues. As hypothesized, fat exhibited substantially higher concentrations than other tissues/organs (Table 2, Figs. 4 and 5). DLM levels in skin were lower, but the skin's relatively large volume and similarly long t resulted in comparable total DLM content 2- and 12-h postdosing (Table 3). Muscle exhibited modest DLM levels, but its large mass (40% of bw) and slow elimination rate resulted in it serving as the third major depot for the parent compound. It is unknown whether DLM binds to muscle, and if so whether this and slow perfusion account for the chemical's long t. It was clear that fat, skin, and muscle were important determinants of DLM's delayed elimination and prolonged duration of action. Judging from comparable tissue t values for 2 and 10 mg/kg, the elimination kinetics of DLM in this dosage range were not dose dependent. Unfortunately, acute neurotoxicity precluded administration of higher doses.
Although blood and tissue time course data are essential for PBTK model development and validation, such data for DLM and other pyrethroids are fragmentary and incomplete. Gray and Rickard (1982) monitored blood and liver DLM levels for just 4 h after giving female rats 1.75 mg/kg iv. Haines et al. (2004) presented, but did not publish, highly variable 4- to 6-h plasma and brain DLM profiles of rats given a very large (30 mg/kg) oral dose. Marei et al. (1982) periodically measured fat DLM levels for 21 days in rats administered 3 mg DLM/kg po. Though Anadón et al. (1996) published 48-h brain, blood, anococcygeus (smooth) muscle, and vas deferens profiles, data are needed for other tissues for modeling. The PBTK model of Mirfazaelian et al. (2006) included the liver, skeletal muscle (slowly perfused tissues), rapidly perfused tissues (set to liver) and fat, as well as brain and blood. Subsequent pyrethroid models should include the skin, in light of the major role it was observed in the present study to play in DLM disposition. As some 83% of DLM in blood was found in the plasma, plasma and rbc subcompartments were utilized in the model of Mirfazaelian et al. (2006). In vivo PCs, calculated in the current investigation as the ratio of each tissue AUC to the plasma AUC, were used as PCs, or distribution ratios in the PBTK model. Serial samples of fat, skin, and muscle were analyzed for their DLM content for up to 504 h postdosing, in order to accurately define the elimination of DLM from these tissues.
In summary, we have characterized the systemic absorption, distribution, and elimination of a necessarily narrow range of oral doses of DLM in adult, male S–D rats. The data were utilized to construct a PBTK model that accurately predicted the disposition of DLM in rats. GI absorption of the insecticide was rapid, but bioavailability was low in the present study. DLM in blood was largely present in plasma. Very small proportions of the absorbed doses reached or remained in the brain. Fat, skin, and muscle ultimately accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Other orally administered pyrethroids may be found to exhibit similar disposition characteristics. Much remains to be learned about major physiological/biochemical processes and barriers that govern the GI absorption, systemic transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans.
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FUNDING |
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U.S. Environmental Protection Agency (STAR grant R830800).
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NOTES |
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1 Present address: Pharmacology Department, National Institute of Toxicological Research, Korea Food and Drug Administration, 5-Nokbum-dong, Eunpyung-gu, Seoul 122-704, South Korea.
2 Present address: DuPont Haskell Global Centers for Health and Environmental Sciences, P.O. Box 50, 1090 Elkton Road, Newark, DE 19714.
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ACKNOWLEDGMENTS |
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We thank S. Muralidhara for his technical assistance.
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REFERENCES |
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Anadón A, Martinez M, Martinez MA, Diaz MJ, Martinez-Larranaga MR. Toxicokinetics of lambda-cyhalothrin in rats. Toxicol. Lett. (2006) 165:47–56.[CrossRef][Web of Science][Medline]
Anadón A, Martinez-Larranaga MR, Diaz MJ, Bringas P. Toxicokinetics of permethrin in the rat. Toxicol. Appl. Pharmacol. (1991) 110:1–8.[CrossRef][Web of Science][Medline]
Anadón A, Martinez-Larranaga MR, Fernandez-Cruz ML, Diaz MJ, Fernandez MC, Martinez MA. Toxicokinetics of deltamethrin and its 4'-HO-metabolite in the rat. Toxicol. Appl. Pharmacol. (1996) 141:8–16.[Web of Science][Medline]
Anand SS, Bruckner JV, Haines WT, Muralidhara S, Fisher JW, Padilla S. Characterization of deltamethrin metabolism by rat plasma and liver microsomes. Toxicol. Appl. Pharmacol. (2006) 212:156–166.[CrossRef][Web of Science][Medline]
ATSDR. Toxicological Profile for Pyrethrins and Pyrethroids (2003) Atlanta, GA: Agency for Toxic Substances and Disease Registry.
Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, Landrigan PJ, Wolff MS. Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environ. Health Perspect. (2003) 111:79–84.[Web of Science][Medline]
Brady JM, Cherrington NJ, Hartley DP, Buist SC, Li N, Klaassen CD. Tissue distribution and chemical induction of multiple drug resistance genes in rats. Drug Metab. Dispos. (2002) 30:838–844.
Casida JE, Gammon DW, Glickman AH, Lawrence LJ. Mechanisms of selective action of pyrethroid insecticides. Annu. Rev. Pharmacol. Toxicol. (1983) 23:413–438.[CrossRef][Web of Science][Medline]
Casida JE, Quistad GB. Golden age of insecticide research: Past, present, or future? Annu. Rev. Entomol. (1998) 43:1–16.[CrossRef][Web of Science][Medline]
Choi J-S, Soderlund DM. Structure-activity relationships for the action of 11 pyrethroid insecticides on rat Na v 1.8 sodium channels expressed in Xenopus oocytes. Toxicol. Appl. Pharmacol. (2006) 211:233–244.[CrossRef][Web of Science][Medline]
Choudhuri S, Cherrington NJ, Li N, Klaassen CD. Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab. Dispos. (2003) 31:1337–1345.
Dewailly E, Mulvad G, Pedersen HS, Ayotte P, Demers A, Weber JP, Hansen JC. Concentration of organochlorines in human brain, liver, and adipose tissue autopsy samples from Greenland. Environ. Health Perspect. (1999) 107:823–828.[Web of Science][Medline]
Foth H, Kahl R, Kahl GF. Pharmacokinetics of low doses of benzo[a]pyrene in the rat. Food Cosmet. Toxicol. (1988) 26:45–51.
Godin SJ, Scollon EJ, Hughes MF, Potter PM, DeVito M, Ross MK. Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats. Drug Metab. Dispos. (2006) 34:1764–1771.
Gray A, Rickard J. The toxicokinetics of deltamethrin in rats after intravenous administration of a toxic dose. Pestic. Biochem. Physiol. (1982) 18:205–215.[CrossRef][Web of Science]
Haines W, Marshall RS, Hunter DL, Padilla S. Pharmacokinetic differences may explain the age-related sensitivity of deltamethrin, a pyrethroid insecticide in rats. Toxicologist (2004) 78:1109.
Heudorf U, Angerer J, Drexler H. Current internal exposure to pesticides in children and adolescents in Germany: Urinary levels of metabolites of pyrethroid and organophosphorus insecticides. Int. Arch. Occup. Environ. Health (2004) 77:67–72.[CrossRef][Web of Science][Medline]
Kim HJ, Bruckner JV, Dallas CE, Gallo JM. Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats. Toxicol. Appl. Pharmacol. (1990) 102:50–60.[CrossRef][Web of Science][Medline]
Kim KB, Anand SS, Muralidhara S, Kim HJ, Bruckner JV. Formulation-dependent toxicokinetics explains differences in the GI absorption, bioavailability and acute neurotoxicity of deltamethrin in rats. Toxicology (2007) 234:194–202.[CrossRef][Web of Science][Medline]
Kim KB, Bartlett MG, Anand SS, Bruckner JV, Kim HJ. Rapid determination of the synthetic pyrethroid insecticide, deltamethrin, in rat plasma and tissues by HPLC. J. Chromatogr. B (2006) 834:141–148.
Lakshmanan MR, Campbell BS, Chirtel SJ, Ekarohita N, Ezekiel M. Studies on the mechanism of absorption and distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. J. Pharmacol. Exp. Ther. (1986) 239:673–677.
Lawrence LJ, Casida JE. Pyrethroid toxicology: Mouse intracerebral structure-toxicity relationships. Pestic. Biochem. Physiol. (1982) 18:9–14.[CrossRef][Web of Science]
Marei AE-S M, Ruzo LO, Casida JE. Analysis and persistence of permethrin, cypermethrin, deltamethrin, and fenvalerate in the fat and brain of treated rats. J. Agric. Food Chem. (1982) 30:558–562.[CrossRef][Web of Science][Medline]
Matthews HB, Surles JR, Carver JG, Anderson MW. Halogenated biphenyl transport by blood components. Fundam. Appl. Toxicol. (1984) 4:420–428.[CrossRef][Web of Science][Medline]
Mirfazaelian A, Kim K-B, Anand SS, Kim HJ, Tornero-Velez R, Bruckner JV, Fisher JW. Development of a physiologically based pharmacokinetic model for deltamethrin in the adult Sprague-Dawley rat. Toxicol. Sci. (2006) 93:432–442.
Rickard J, Brodie M. Correlation of blood and brain levels of the neurotoxic pyrethroid deltamethrin with the onset of symptoms in rats. Pestic. Biochem. Physiol. (1985) 23:143–156.[CrossRef][Web of Science]
Ross MK, Borazjani A, Edwards CC, Potter PM. Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem. Pharmacol. (2006) 71:657–669.[CrossRef][Web of Science][Medline]
Roth WL, Freeman RA, Wilson AG. A physiologically based model for gastrointestinal absorption and excretion of chemicals carried by lipids. Risk Anal. (1993) 13:531–543.[CrossRef][Web of Science][Medline]
Soderlund DM, Casida JE. Substrate specificity of mouse-liver microsomal enzymes in pyrethroid metabolism. Am. Chem. Soc. Symp. Ser. (1977) 42:162–172.
Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, Stevens JT, Weiner ML. Mechanisms of pyrethroid neurotoxicity: Implications for cumulative risk assessment. Toxicology (2002) 171:3–59.[CrossRef][Web of Science][Medline]
Sudakin DL. Pyrethroid insecticides: Advances and challenges in biomonitoring. Clin. Toxicol. (2006) 44:31–37.[CrossRef][Web of Science]
Tanabe S, Nakagawa Y, Tatsukawa R. Absorption efficiency and biological half-life of individual chlorobiphenyls in rats treated with Kanechlor products. Agric. Biol. Chem. (1981) 45:717–726.[Web of Science]
Wang S-Y, Barile M, Wang GK. A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na(+) channels is critical for pyrethroid action. Mol. Pharmacol. (2001) 60:620–628.
Wang X, Santostefano MJ, Evans MV, Richardson VM, Diliberto JJ, Birnbaum LS. Determination of parameters responsible for pharmacokinetic behavior of TCDD in female Sprague-Dawley rats. Toxicol. Appl. Pharmacol. (1997) 147:151–168.[CrossRef][Web of Science][Medline]
Whyatt RM, Camann DE, Kinney PL, Reyes A, Ramirez J, Dietrich J, Diaz D, Holmes D, Perera FP. Residential pesticide use during pregnancy among a cohort of urban minority women. Environ. Health Perspect. (2002) 110:507–514.[Web of Science][Medline]
Wolansky MJ, Gennings C, Crofton KM. Relative potencies for acute effects of pyrethroids on motor function in rats. Toxicol. Sci. (2006) 89:271–277.
Zhang Y, Benet LZ. The gut as a barrier to drug absorption: Combined role of cytochrome P450 3A and p-glycoprotein. Clin. Pharmacokinet. (2001) 40:159–168.[CrossRef][Web of Science][Medline]
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