Application of Gas Chromatography-mass Spectrometry in Analyzing Pharmacokinetics and Distribution o

426Biomed Environ Sci, 2014; 27(6): 426-435Original ArticleApplication of Gas Chromatography-mass Spectrometryin Analyzing Pharmacokinetics and Distribution ofEL SEVIERDeltamethrin in Miniature Pig TissuesZHU Pan'2, FAN Sai', Z0U Jian Hong', MIAO Hong2#, LI Jing Guang'2,ZHANG Guo Wen'#, and WU Yong Ning'2I. State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, Jiangxi, China;2. Key Laboratory of Food Safety Risk Assessment of Ministry of Health, China National Center for Food SafetyRisk Assessment, Beijing 100021, China; 3. Institute of Nutrition and Food Safety, Beijing Centre of DiseaseControl and Prevention, Bejing 100013, China; 4. The Second Arillery General Hospital, Bejjing 100088, ChinaAbstractObjective To characterize the pharmacokinetics and distribution profiles of deltamethrin in miniaturepig tissues by gas chromatography-mass spectrometry (GC-MS).Methods Pharmacokinetics and distribution of deltamethrin in blood and tissues of 30 miniature pigswere studied by GC-MS after oral administration of deltamethrin (5 mg/kg bw). Data were processed by3P97 software.Results The serum deltamethrin level was significantly lower in tissues than in blood of miniature pigs.The AUCo-72 h, Cmax, of deltamethrin were 555.330+316.987 ng h/mL and 17.861+11.129 ng/mL,respectively. The Tmax, of deltamethrin was 6.004+3.131 h.Conclusion The metabolism of deltamethrin in miniature pigs is fit for a one-compartment model witha weighting function of 1/C. Deltamethrin is rapidly hydrolyzed and accumulated in miniature pigtissues.Key words: Deltamethrin; Miniature pig; Pharmacokinetics; Tissue distribution; GC-MSdoi: 10.3967/bes2014.035ISSN: 0895-3988www.besjournal.com (full text)CN: 11-2816/QCopyright⑥2014 by China CDCINTRODUCTIONcommonly used type |I pyrethroid (Figure 1), isavailable as a single isomer'. DLM， with a lowyrethroids representing an increasingpersistence and high effectiveness, is widely used inproportion of pesticide sale around theagriculturel. DLM，as one of the_ most potentworld, especially in the United States'neurotoxicantsofpyrethroids',inducesare extensively used in agriculture, forestry andneurotoxicity by slowing down the opening andpublic health due to their insecticidal potency, slowclosing of voltage-gated sodium channels'pest resistance, and relatively low acute toxicity'".voltage-gated calcium channes'!,and/or bothTraditionally, pyrethroids are divided into type I andsodium and calcium channels". Human exposure totype |I according to their structures and toxicologicalDLM via dermal contact and ingestion may causeactions. Compared to type 1, type |I contains anacute poisoning with symptoms of rashes, blistering,additional cyano group. Deltamethrin (DLM)， asore throat, nausea, abdominal pain, or even loss of"This work was supported by the National Natural Science Fou中國煤化工4 and No. 2012CB720804."Correspondence should be addressed to MIAO Hong, Tel: 86:YHCNMHG1g0827@163.com; ZHANGGuo Wen, Tel: 86-791-83969532, E-mail: gwzhang@ncu.edu.cnBiographical note of the first author: ZHU Pan, female, born in 1987, PhD candidate, majoring in nutrition and foodsafety.Received: April 5, 2013;Accepted: June 5, 2013Biomed Environ Sci, 2014; 27(6): 426-435427Baoding (Hebei, China). Acetone, cyclohexane, andethyl acetate of chromatographic grade wereBr、▲Hpurchased from Fisher Company (Fisher Scientific,Fairlawn, NJ, USA). Petroleum ether and hexane ofchromatographic grade were purchased from J. T.Figure 1. Chemical structure of DLM.Baker Company (Phillipsburg, NI, USA). Florisil solidphase extraction cartridges (2 mg, 12 mL, 20/PK)were purchased from Agilent Technologies (Palo Alto,consciousness'It is thus important to study itsCA，USA). Guaranteed reagents of anhydrousabsorption,distribution, andmetabolism inmagnesium sulfate and sodium chloride weremammalian species, in order to assess its risk topurchased from Chemical Reagent Company inhealth.Beiing. Water was produced in the Milli-Q ultra-purePrevious studies have been mainly focused onwater system.the determination, toxicity and metabolism of DLMin different animals. Galetin et al.2 reported thatExperimental Design of Miniature Pigsthe absorption and distribution of pyrethroids inThirty miniature pigs weighing 20-25 kg werehumans are similar to the findings in otherpurchased from Beijing Institute of Animalmammalian species. Pigs, which are more similar toHusbandry and Veterinary Institute,Chinese[13-15]humans'，are more suitable than otherAcademy of Agricultural Sciences. The miniature pigsmammalian species for studying the metabolism andwere acclimated to standard housing anddistribution of DLM. Thus, the absorption andenvironmental conditions for 1 week prior to thedistribution manners of DLM in pig tissues may bestudy.more helpful for corresponding studies in humans.Eighteen miniature pigs were divided into 6Pharmacokinetics (PK) is a comprehensive studyexperimental groups (3 in each) and anotherwithconcurrentdistribution,3 pigs served as control. The animals in experimentalmetabolism, and elimination of DLM by determininggroups were administered orally with DLMthe target organ dose of toxic moiety over time, and(5 mg/kg bw) dissolved in vegetable oil, and those inin turn the magnitude and duration of toxicity16-17.the control group were given orally vegetable oil.Mirfazaelian et al.ua, Kim et al.5 and Tornero-VelezDistribution of DLM in their tissues were detectedet al.l19] revealed that adipose tissue, skin, and(Figure 2).skeletal muscle are the major depots for DLM, andAll animals were used in accordance with thethe Tmax is relatively long. Godin et al.20-21 showedGuidelines for the Care and Use of Laboratorythat liver is the primary metabolic organ for clearingAnimals (NIH Publication No. 85-23, revised 1996).DLM.AlI procedures were approved by the Animal CareUntil now， no report is available on PK,Review Committee, China Agricultural University.distribution and disposition of DLM in pig tissues. In:he present study, miniature pigs were used as anSample Collectionanimal model to assess PK， absorption ancBlood samples (10 mL) were taken from jugulardistribution of DLM in pig tissues. Furthermore, DLMin blood and tissues of miniature pigs wereveinat0,0.5,1,2,3,4,6,9,12,24,36,and72h,respectively, after DLM treatment. Pigs werequantifiedbychromatography-massspectrometry (GC-MS). The results are critical for thesacrificed at 3, 6, 12, 24, 36, and 72 h, respectively,after oral DLM. Heart, liver, spleen, lung, kidney,assessment of risk in humans exposed to DLM.brain，muscle, and fat tissues were collected,homogenized and stored at -80 °C.MATERIALS AND METHODSPretreatment of Blood SamplesChemicals and MaterialsFive mL blood was placed into a polypropyleneThe standard DLM and ds-trans-cypermethrincentrifu1co tuho. ond. 1∩∩ 川dg-trans-cypermethrinwith its purity higher than 98% were purchased from50中國煤化工hich 30 mL acetone:Dr. Ehrenstorfer GmbH (Augsburg, Germany). DLMi YHCNMHGsolution,1gsodium)f industrial grade with a purity of 80.83% waschToride," 4 g anhydrous magnesium sulfate wereprovided by Spark Technical Research Institution ofadded. The mixture was extracted by ultrasonication428Biomed Environ Sci, 2014; 27(6): 426-435for 30 min and centrifuged at 10 000 rpm for 5 min.spectrometer in negative chemical ionization (NCI)The supernatant was transferred and dried at 38 °C.mode. Separations were achieved on a VF5-MSThe residues were reconstituted by 5 mL hexane,capillary column (30 mx0.25 mm i.d.x0.25 μm,and concentrated to 1 mL under a gentle stream ofVarian, Las Vegas, NV, USA). Selected ion monitoringnitrogen at 40。C for further solid-phase extraction(SIM) was chosen to increase its sensitivity. Samples(SPE) purification. The Florisil cartridge was condi-were introduced in split-injection mode (20:1) attioned with 5 mL hexane, and the extract was then260 °。C and the oven temperature was ramped fromapplied onto the cartridge. The loading fraction and80 to 290。C at 15。C/min, held at 290 for 10 min andfractions eluted by 9 mL hexane: acetone (95:5, v/v)then raised to a final temperature of 300 °C at a ratesolution were collected and dried. The residues wereof 20。C/min and held for 5 min. High purity heliumredissolved in 1.0 mL hexane for GC-MS analysis.(9>99.999%) was used as the carrier gas with thecolumn flow of 1.0 ml/min. The temperatures of thePretreatment of Tissue Samplesion source and manifold were 250 。C and 40 °C,Homogenized tissue samples (1.00 g for fat,respectively. The electron energy was 70 eV and5.00 g for the others) containing 100 μL internalelectron multiplier was 1000 V. The monitored SIMstandard (1.0 mg/L ds-trans-cypermethrin), 30 mLions were m/z 79, 81, 137, 297 for DLM, and m/z 177,solution of acetone: petroleum ether (1:1, v/v), 2 g179213，215fordc-trans-cypermethrin.sodium chloride and 8 g anhydrous magnesiumQuantitative ions were selected at m/z 79 for DLM,sulfate were subjected to ultrasonic extraction forat m/z 213 for d-trans-cypermethrin. The30 min. After centrifugation at 10 000 rpm for 5 min,chromatogram is shown in Figure 3.the supernatants were transferred and the residuesCalibration Curves and Quality Controlwere extracted for one more time. The twosupernatants were combined and dried. The residuesThe internal standard calibration by d;- trans-were reconstituted by 10 mL cyclohexane: ethyIcypermethrin was used for the quantitative analysis.acetate (1:1, v/v) and purified by gel permeationThe calibration series were constructed in hexanechromatography (GPC) on the column of C0785with a known amount of DLM. The calibration series(25x250 mm， Accuprep MPSTM， J2 Scientific,were 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, and 5 mg/L,Columbia, USA) at the mobile phase of cyclohexane:with 0.1 mg/L of d-trans-cypermethrin.ethyl acetate (1:1, v/v) at a flow rate of 4.7 ml/min.The quality control (QC) samples were made byThe fractions at 8-14 min were collected and dried.blank samples with a spiked known amount of DLM.The residues were reconstituted by 0.5 mL hexane forThe QC samples were pretreated as the blood orGC-MS analysis.tissue samples and performed at a low spiked level(0.01 mg/kg for tissues, and 0.01 mg/L for blood,GC-MS AnalysisLQC), a medium spiked level (0.02 mg/kg or mg/L,GC-MS analysis was carried out with a VarianMQC) and a high spiked level (0.20 mg/kg or mg/L,450 gas chromatograph plus Varian 320 massHQC). The recovery of QC samples should be in theAdministeredPurchasing with DLMSampling at6h12 h24 h36 h72 hTissueDistributionBlank: Administered with Vegetable OilStudiesBlank: Administered with Vegetable 0ilBlood1 weekPharmacokineticsBlank Samples were Collected at 0, 0.5, 1, 2,3, 4, 6, 9, 12, 24, 36, and 72 hAcclimationafter dosing中國煤化工Adiministeredwith DLMTYHCNMHGFigure 2. Distribution of DLM in pig tissues.Biomed Environ Sci, 2014; 27(6): 426-435429range of 60%-120% with a relative standardMatrix Effectdeviation (RSD) less than 20%.DLM standards in solvent and matrix extractsData Analysiswere injected into GC-MS to evaluate the matrixData were analyzed using the 3P97 PK softwareeffect. The results showed that response of DLM in(Chinese Mathematics & Pharmacological society) indifferent tissues and blood samples neithera one-compartment model, and a weighting functionincreased nor decreased compared with that inof 1/C' for data ftting and parameter estimation. PKsolvent. Therefore, the calibration curve plotted wasparameters of blood and tissue were calculated,preferred.including absorption half-time (r/2(ka), eliminationLinearity and Limit of Detectionhalf-life (T1/2(ke), time for maximal concentration(Tmax), maximal concentr ation (Cmax), mean retentionThe standard calibration curves were linear overtime (MRT), area under AUC, total body clearance asa range of 0.001-5 mg/L with the correlationa function of bioavailability (CI/F) and volume ofcoefficienthigher than 0.999. The GC-MSdistribution (V/F).chromatograms of different blank matrix and tissuesamples are shown in Figure 4.RESULTSLimit of detection (LOD) and limit ofquantitation (LOQ) were determined as the analyteSelectivity and Stabilityconcentrations. The LOD and LOQ for DLM were 0.1and 0.3 ug/L for blood sample and 0.1 and 0.3 ug/kgAs shown in Figure 4, good selectivity wasfor tissue sample.obtained, and no Interference peaks to DLM 0Recovery Studiesinternal standard in different matrices were found.Analyte stability of freeze-thaws, long-term andThe accuracy and precision of the method wereshort-term in different matrices, was tested usingexpressed as the results of inter- and intra-dayLQCS and HQCs. The frozen and thawed samplesreproducibility. LQCs， MQCs， and HQCs of 6were tested for long-term and short-term stability.replicates were analyzed according to the procedureThe results showed that the stability of freeze-thawsas previously described. As shown in Table 1, thewas acceptable with a deviation less than 5%. Theintra-andinter-dayrecoveries of DLM wereextracts from blood and tissue samples were stable88.8%-113.1% at the concentrations of 0.01, 0.02,at least for 2 weeks at -20。C.and 0.20 mg/L with the cofficient of variation <10.9%,10.0d-cypermethrin7.53]deltamethrin5.012.5日0.0士11718minutesBP:213.1 16.191 min, Scan:637 Merged, RIC: 9.167e+6.BC,BP:79.3 18.563 min, Scan:2004 Merged, RIC:29.867e+6.BC100%213.13.405e+679.375%1.252e+6177.2.50%1.301e+625%手25%)%毛19000210 m/中國煤化工30”" 350 m/zAcquired RangeYHCNMH GFigure 3. Chromatogram of DLM standard and d-trans-cypermethrin (0.02 mg/L).430Biomed Environ Sci, 2014; 27(6): 426-435which demonstrated a good precision and accuracycharacterized by its peak at 6.00 h, and the AUCo-72hfor the current method.was 555.33+316.99 ng h/mL. Meanwhile, the MRTwas 14.92 h, indicating that DLM was slowlyPK of DLM in Miniature Pig Blood Sampleeliminated at a rate of 0.011 mI/h.The average concentration of DLM in bloodConcentrations and PK Parameters of DLM insample at 12 different time points was fit for theMiniature Pig Tissue Samplesone-compartment model with a weighting functionof 1/C. The mean blood concentration-time curveThe concentrations of DLM in different tissuefor DLM is shown in Figure 5. Oral DLM could besamples are shown in Table 3. In general, the DLMdetected in blood sample at 30 min, the serum levelresidue level was low in different tissue samplesof DLM increased rapidly and reached its peak (17.86except that (1.98 mg/kg) in fat tissue sample. The datang/mL) at 6 h, and then decreased slowly until 72 hanalyzed by 3P97 software for the model predictionswith no DLM detected.and time curves are shown in Figure 6. The curvesThe blood PK parameters are summarized incould clearly show the absorption, distribution andTable 2. After oral DLM, its enterohepatic circulationelimination of DLM in different tissue samples. Thewas demonstrated. The T1/2(Ka) and T1/2(Ke) wereelimination tendency of DLM was similar in all tissue2.68 h and 20 h, respectively. The Tmax for DLM wassamples except in liver tissue sample.40a)3.5| (b)20 (c), Blood3.015/Liver; 30|考2.0? 20g1g 1./ Heart2 1.010)Blank0.,Blank/Blankou1617”181920[6178.1920~1617181920min20] (d)25 (e)3.51 (), Spleen15|,Lung號1:2.010g 1.5, Kidney1.0s|1617“1819201617 18. 19 20~20] (g)5 (h)3.5| (0), Muscle, Fat2.e 2.0318 1.5Blank Brain16 1718. 19 2018 1920~16.0 16.5 17.0 17.5 18.018.5 19.0Figure 4. Chromatograms of DLM in blood (a), heart (b),中國煤化工), kidney (f), muscle(g), fat (h), brain (i) and their blank matrix samples.MHCNMHGBiomed Environ Sci, 2014; 27(6): 426-435431Table 1. Method Validation in Different MatricesIntra-day (n=6)Inter-day (n=6)TissueSpikedType(mg/kg)Calibration CurveAccuracyPrecision(%)(RSD%)0.01108.94.790.16.9Blood0.02Y=0.4688X-0.05340.9992109.588.86.40.20.796.19.092.65.195.1.8HeartY=0.8256X-0.01080.999698.3.697.5105.95.3102.77.292.4.997.3LiverY=0.4829X-0.082230.999490.0.595.3.491.899.510.994.63.895.25.7SpleenY=0.4752X+0.00230.99971.197.45.296.296.895.82.797.23.6LungY=0.4691X-0.009494.22.696.998.42.399.9101.2KidneyY=0.5012X-0.00350.9998102.46.198.6102.95.4101.76.3101.33.2102.5MuscleY=0.4940X+0.002898.7.399.1100.599.7109.47.9108.37.4FatY=0.5349X-0.03890.9993107.26.5104.98.7103.1101.6100.9BrainY=0.2946X-0.0134100.4102.4.6100.7101.6 .4.1Table 2. PK Parameters of Oral DLM in Blood Sample(meantSD, n=6)尼25ParametersUnitValue了≌20T121K2a)2.680+1.919g 15-T/21Kel20.169+16.546o6.004+3.1315C (max)μg/L17 .861+11.129102030一405060708010 h/I555.330+316.987Time (h)中國煤化工14.929+7.560Figure 5. Blood concentration-time profilesYHCNMHG0.011+0.006of oral DLM (5 mg/kg bw) in miniature pigsV/F (c)L/kg0.339+0.397(n=6, meantSD).432Biomed Environ Sci, 2014; 27(6): 426-435Table 3. Concentration of Oral DLM in Different Tissue Samples at Different Time Points (n=3, mg/kg)TimeHeartLiverSpleenLungKidneyBrainFatMuscle3h0.0210.0110.2040.056.0150.4180.035;h0.1700.0090.0150.1250.0320.0190.72012 h0.3830.0240.1080.1210.0231.9840.09324h0.1300.00030.0040.0430.0420.7190.01836 h0.0020.0170.0130.0200.1340.0050.008NDNote. not detected.g 2.000復180.000， 1.800色160.000 |E 1.600140.0001.400120.0001.200100.0001.000 |80.000.800 I60.000言0.60040.000; 20.000: 0.200 tI量000010 2030405060 70 800.0000+ 204508Time (h)。350.000豆30.000海30.0000蘭25.000250.00020.000200.00015.000150.00010.0005.00050.000房0001020304050607)8(0.000102030405060708o更80.000 [畫(huà)40.000魚(yú)70.000魚(yú)35.00030.00025.0004.000 ]I820.0003 10.000- I主10.000 I2 0.0000203040506070 80000510.2030405o60芯803 愈70.0001 200.000色60.000「品1 00.000后50.000800.000e 40.000600.000岳30.000400.000。20.000告10.000= 0.0000.0005- 10203040506070 80Figure 6. Model predictions and time course concentratil中國煤化工liver (b), spleen (c),lung (d), kidney (e), brain (f), muscle (g), fat (h) ti:MYHC NMH Gure pigs after oraladministration (n=3, meantSD).Biomed Environ Sci, 2014; 27(6): 426-435433The calculated PK parameters of DLM inwas 1 and 2 h, respectively, after oral administrationdifferent tissue samples are listed in Table 4. Theof 10 mg/kg DLM!22, which corresponded with theT1/2(Ka) was 0.387-4.772 h, and the T1/2(Ke) was >7 h,results of 17.861 μg/L blood and 0.025 μg/g brain inindicating that the DLM was slowly eliminated irminiature pigs after oral administration of 5 mg/kgtissues. The Cmax was 0.01-1.23 mg/kg, and the TmaxDLM in the present study. It was reported that DLMwas 1.997-11.390 h. The AUCo.72h was higher in fatcould be detected at 8.3 h in plasma of adult SD ratsand heart tissue samples than in liver and brainadministered orally with 20 mg/kgThesetissue samples. Similar trends were found for CI/F(s)differences could be ascribed to the different animaland V/F(c).species and dosages. The DLM residue level was lowin different tissues of pigs, which is consistent withDISCUSSIONthe reported levelLittle information is available on the location ofFew studies are available on pharmacokineticsabsorption of pyrethroids in humans and otherand distribution of DLM in experimental animals. Inexperimental models except for SD rats. It wasthe present study, the pharmacokinetics, absorption,presumed that pyrethroids crossed the intestinaldistribution, and metabolism of DLM in miniaturecells due to the large exposed surface area andpigs were described. Since their dietary habit,passed into the enterohepatic circulation bydigestion mode, hematological and hematochemicaldiffusing across lipid membranes5o. Generally, DLMconstants, and viscera weights are more similar toare rapidly absorbed by combing lipid membranes ofhumans[13-15,, the absorption and distribution of DLMred blood cells after oral administration, and reachin miniature pigs may be more helpful fordifferent tissues/organs with circulation bycorresponding studies in humans.diffusion5. The absorption,elimination andFurthermore, a GC-MS-SIM method wasmetabolic rate, and distribution pattern are ratherdeveloped for the determination of DLM in blooddifferent in different tissues. In the present study,and tissue samples from miniature pigs with twcDLM were accumulated in fat, heart and muscledifferent novel cleanup procedures. Kim et al.22tissues, rapidly eliminated in liver and hardlyanalyzed DLM in plasma, liver, kidney, and braindetected in liver at the last time phase. Liver is thetissue samples by HPLC with the LOD of 10 μg/L. Themajor metabolic organ for detoxifying pesticides52- 3,LOD was lower in the present study than in previouswhich can explain the rapid elimination of DLM instudies (0.1 ug/L vs 1 μg/L and 5 μg/L3-24]liver. Our results are consistent with the reportedThe 3P97 software is widely applied infindingsl'0,34. In this study, DLM were absorbedcalculating the pharmacokinetic parameters andslowly. The Tmax was 6 h and the bioavailability ofAUCo: in different tissues'h5 26. The pharmacokineticDLM was much lower than that in previousparameters in the present study were different fromstudiesn8.2. It might be anticipated that oil can actthosein previous studiesl22,27.The Cmax ofas a reservoir in the gut to delay the absorption of0.95 ug/mL plasma and 0.21 μg/g brain in adult ratsDLM/351.Table 4. Pharmacokinetic Parameters of Oral DLM in Tissue Samples from 6 Miniature Pigs (meantSD)ParametersUnitHeartLiverSpleenLungKidneyBrainMuscleFaT12IKw)4.772+2.0051.756+0.9732.121+0.3265.210+0.2414.611+1.3550.387+0.1090.459+0.0543.870.338h7.089+3.08210.821+481239.613+14.501 11.5301.026 15.196+4.792 12.337+4.762 20.045+2.311 11.013t0546Tmx8.337+4.2435.499+2.5919.465+2.2319.322+0.79811.390+4.293 1.997+0.6382.560+0.2409.003+0.546mg/g 0.282+0.1400.013+0.0040.016+0.01130.174+0.03950.065+0.0030.02540.0070.0610.0021.233+0.250AUGozh .mgh/kg 6.519+3.2510.289+0.1281.083+0.2473.741+0.8792.404+0.9840.502+0.1041.943+0.319 34.537+1.380l/F(S)L/hkg) 0.670.15917.295+69244.618+2. 869.1.337+0.4502.080+0.8639.964+2.3102.574+0.914 0.145+0.0176/F(c)L/kg7.844+2.984 170.014+62.652 263.928+96575 22.705+3.41中國煤化工7421.4842.300+0.132Note." The model fits for the one-compartment modelMHC N M H Gof 1/C' while the otherswith a weighting function of 1.434Biomed Environ Sci, 2014; 27(6): 426-435DLM are widely and rapidly distributed in fat,5. Kim KB, Anand Ss, Kim H, et al. Toxicokinetics and tissuedistribution of deltamethrin in adult Sprague-Dawley rats.brain and skeletal musclelb9. It was reported thatToxicol Sci, 2008; 101, 197-205.DLM concentration was higher in central nervous6. Samatha K and Sreedhar N. Polarographic determination ofsystem than in plasma after oral administration5o. Indeltamethrin. Talanta, 1999; 49, 53-8.this study, the highest DLM residue level (1.23 mg/kg)7. Eriksson P and Fredriksson A. Neurotoxic effects of twodifferent pyrethroids， bioallethrin and deltamethrin, onwas observed in fat tissue sample, and the Tmax wasimmature and adult mice: changes in behavioral andapproximately 9 h after initial exposure. Akhtar etmuscarinic receptor variables. Toxicol Appl Pharmacol, 1991;al.37reported thatpermethrin and/or it108, 78-85.metabolites were detected in fat tissue from Cows8. Soderlund DM. State-dependent modification of voltage-gatedsodium channels by pyrethroids. Pestic Biochem Phys, 2010;on day 9 after oral dosing, suggesting that DLM was97, 78-86.mainly stored in fat tissue. Meanwhile, the peak. Neal AP, Yuan Y, and Atchison WD. Allethrin diffentiallyconcentration of DLM was 0.03 mg/kg in brain tissuemodulates voltage-gated calcium channel subtypes in rat PC12sample from miniature pigs at 2 h after oralcells. Toxicol Sci, 2010; 116, 604-13.administration (Figure 6 h) and then rapidly declined,10.Shafer TJ and Meyer DA. Effects of pyrethroids onvoltage-sensitive calcium channels: a critical evaluation ofindicating that the metabolic process of DLM in thestrengths, weaknesses, data needs, and relationship tobrain was not mediated by metabolism. The resultsassessment of cumulative neurotoxicity. Toxicol Applare in accordance with the previous findings'3e .Pharmacol, 2004; 196, 303-18.Sathanandam et al.59 displayed that DLM was11.Bradberry SM, Cage SA, Proudfoot AT, et al. Poisoning due topyrethroids. Toxicol Rev, 2005; 24, 93-106.rapidly distributed in nerve tissues with a12.Galetin A and Houston JB. Intestinal and hepatic metabolicdistribution half-time of 2.1 h in rats after givingactivity of five cytochrome P450 enzymes: impact onsingle oral dose, showing that DLM mightprediction of first pass metabolism. J Pharmacol Exp Ther,2006; 318, 1220-9.accumulate in brain due to its relatively high blood13.Feng ST, Li K, Mu YL, et al. Inbreeding line culture of Wuzhishanflow and lipid content.Mini-pig and the innovation in nurturing inbred for Chineseconclusion, a sensitive GC-MS method hasgenetic resources. J Agr Biotech, 2012; 20, 849-57.been established for the quantification of DLM in14.Yang S, Ren H, Wang H, et al. Investigation on the hematologyblood and tissues. 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