30. Sheriffdeen, MM; Alehaideb, ZI; Law, FCP. (2019) Caffeine/Angelica dahurica and caffeine/Salvia miltiorrhiza metabolic inhibition in humans: In vitro and in vivo studies.Complement. Ther. Med. 46: 87-94 Caffeine/Angelica dahurica and caffeine/Salvia miltiorrhiza metabolic inhibition in humans: In vitro and in vivo studies
Caffeine; Cytochrome; Furanocoumarin; Pharmacokinetic interaction; Tanshinone
Background: caffeine is a major constituent in numerous foods, beverages, dietary supplements and medications.Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Say, and Salvia miltiorrhiza Bunge are traditional medicines commonly used in Asia. Objectives: to compare the pharmacokinetics of caffeine in humans before and after consuming an aqueous extract of A. dahurica or S. miltiorrhiza, and to propose a mechanistic explanation for in vivo caffeine metabolism inhibition based on in vitro data obtained with human liver microsomes. Methods: Each of the four human volunteers was given a single oral dose of caffeine before and after consuming an A. dahurica or S. miltiorrhiza extract. Saliva samples were collected from the volunteers at pre-determined time points after receiving caffeine. The saliva samples were analyzed for unchanged caffeine using liquid chromatography. Results: A. dahurica and S. miltiorrhiza extracts were capable of inhibiting caffeine metabolism in the human volunteers. In a separate study, cytochrome (CYP) 1A2-mediated caffeine demethylase activity was studied in incubation containing human liver microsomes, p-nicotinamide adenine dinucleotide phosphate, and an herbal extract (or a pure bioactive chemical from the herbs). In all cases, CYP1A2 activity was decreased with an increasing inhibitor concentration, confirming the inhibition of caffeine metabolism in vivo. Caffeine metabolism inhibition most likely involved the competitive and/or non-competitive mechanism. Conclusion: Because a high level of caffeine in the plasma may result in adverse health effects in humans, care must be exercised when caffeine is consumed together with A. dahurica or S. miltiorrhiza. DOI PubMed
29.Law, FCP; Yao, M; Bi, HC; Lam, S. (2017) Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.Pharmacol. Res. Perspect. 5 Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans
PBPK model; tea catechins; systemic dosimetry
Although green tea (Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products. DOI
28. Shieh, BHH; Louie, A; Law, FCP. (2016) Factors Affecting Distribution of Estrogenicity in the Influents, Effluents, and Biosolids of Canadian Wastewater Treatment Plants.Archives of Environmental Contamination and Toxicology 70: 682-691 Factors Affecting Distribution of Estrogenicity in the Influents, Effluents, and Biosolids of Canadian Wastewater Treatment Plants
Canadian wastewater treatment plants (WWTPs) release significant amounts of estrogenic chemicals to nearby surface waters. Environmental estrogens have been implicated as the causative agents of many developmental and reproductive problems in animals, including fish. The goals of this study were to assess the estrogenic activity in the influents, effluents, and biosolids of thirteen Canadian WWTPs using the yeast estrogen screen (YES) bioassay and to investigate whether factors, such as wastewater treatment method, sample storage, extraction efficiency, population, and summer/winter temperature had any effects on the distribution of estrogenicity in the WWTPs. Results of the study showed that estrogenicity from the influent to the effluent decreased in seven WWTPs, increased in two WWTPs, and did not change in four WWTPs during the winter. Estrogenic concentrations generally decreased in the order of biosolids > influents > effluents and ranged from 1.57 to 24.6, 1.25E-02 to 3.84E-01, and 9.46E-03 to 3.90E-01 ng estradiol equivalents/g or ml, respectively. The estrogenicity in the final effluents, but not those in the influents and biosolids, was significantly higher in the summer than the winter. Among the WWTP treatment methods, advanced, biological nutrient removal appeared to be the most effective method to remove estrogenic chemicals from wastewaters in Canada. Our studies help to identify factors or mechanisms that affect the distribution of estrogenicity in WWTPs, providing a better understanding on the discharges of estrogenic chemicals from WWTPs. DOI
27. Hunter, S; Khan, MZ; Shieh, BHH; Doerr, B; Ali, S; Law, FCP. (2012) Assessing Estrogenic Chemicals in Anchovy and Mussel Samples from Karachi, Pakistan with the Yeast Estrogen Screen Bioassay.Bulletin of Environmental Contamination and Toxicology 89: 990-994 Assessing Estrogenic Chemicals in Anchovy and Mussel Samples from Karachi, Pakistan with the Yeast Estrogen Screen Bioassay
Estrogenic activity; Yeast estrogen screen; Pakistan; Aquatic species
Endocrine disrupting chemicals (EDCs) are introduced into the aquatic environment through industrial and municipal effluents along with urban and agricultural runoffs. Exposure of aquatic organisms to EDCs may lead to hormonal disruption and adverse health effects. The goals of our study were: to collect anchovy and mussel samples from the coastal region of Karachi, to use the yeast estrogen screen (YES) bioassay in estimating xeno-estrogen content in these samples, and to investigate if the bioassay could be used to quantify known amounts of 17 beta-estradiol (E2) injected into cod and salmon fillets. Results of the studies showed that mussel estrogenic activity in Karachi decreased in the order of Buleji point 1 (8.91 +/- A 4.77, mean +/- A SD) > Paradise point 1 (1.72 +/- A 0.81) > Paradise point 2 (0.61 +/- A 0.84) ng E2 equivalents/g wet wt (p < 0.05). By comparison, anchovy estrogenic activity at Korangi/Phitti Creek was much higher than at Manora. Together, these results confirmed previous reports that both Buleji point 1 and Korangi/Phitti Creek were the most contaminated areas of Karachi. The YES bioassay was only a semi-quantitative method in determining the contents of xeno-estrogens in aquatic organisms; it consistently overestimated the amounts of E2 injected into cod and salmon fillets due to additive and/or non-additive interactions between E2 and endogenous estrogens. Nevertheless, the YES bioassay was able to identify the contaminated sites in the coastal region of Karachi. DOI
26. Sara FM Ali, Ben HH Shieh, Zeyad Alehaideb, MZ Khan, Alvin Louie, Noor Fageh and Francis CP Law. (2011) A Review of the Effects of Some Selected Pyrethroids and Related Agrochemicals on Aquatic Vertebrate Biodiversity.Canadian Journal of Pure and Applied Sciences 5: 1455-1464 A Review of the Effects of Some Selected Pyrethroids and Related Agrochemicals on Aquatic Vertebrate Biodiversity
Pollution in the aquatic ecosystem by pesticides, their metabolites and by-products is considered critical in the conservation of biodiversity and natural resources. Several studies have reported the toxicological issues and adverse effects of pesticides in aquatic biodiversity. After the development of the field ecotoxicology, researchers have expanded their studies towards the effects of pesticides in aquatic ecosystems. Pesticides containing chemicals such as Pyrethroids, cypermethrin, deltamethrin, cyphenothrin and other related compounds have been shown to cause adverse effects on the development, behaviour and mortality of different species of fish, birds, amphibians and aquatic mammals. This review article summarizes the adverse impact of the use of pesticides and related agrochemicals in populations of aquatic, amphibian and avian species.PDF
25. Li, LZ, Shun, Z Qiumin, FCP Law. (2010) Pharmacokinetics of imperatorin in the plasma and liver of rats.Traditional Chinese Drug Research & Clinical Pharmacology, Year 2010 , Issue 6 , Page 624-626 [Chinese Journal]Pharmacokinetics of imperatorin in the plasma and liver of rats
22. Gao, GH; Law, FCP. (2009) Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA.Drug Metabolism and Disposition 37: 884-891 Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA
CHROMATOGRAPHY-MASS SPECTROMETRY; LIQUID-CHROMATOGRAPHY; MODELS; PLASMA; DISPOSITION; PREDICTION; HUMANS; PERFORMANCE; OXYMATRINE; PARAMETERS
ACAPHA, a botanical drug for the treatment of human esophageal cancer in China, is under investigation as a lung cancer chemoprevention agent at the BC Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of matrine, a bioactive marker of ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model for pure matrine; and to characterize the absorption and clearance of crude matrine in ACAPHA-treated rats using the PBPK model. Pure matrine (15 mg/kg) or crude matrine in the form of ACAPHA (0.38 or 3.8 g/kg) was administered to the rat by gavages. The rats were sacrificed at different time points postdosing. Blood and major organs were removed from the rat, extracted with toluene/butanol, and quantified for matrine using gas chromatography-mass spectrometry. An 11-compartment, flow-limited PBPK model of matrine was developed. The PBPK model was able to simulate closely the empirical data of rats treated with pure matrine. Because the absorption and clearance of crude matrine in ACAPHA-treated rats could not be parameterized a priori, they were estimated by fitting the experimental data to the PBPK model. Results of the study show that pure matrine is absorbed and eliminated by the rat at faster rates than crude matrine. Moreover, the ACAPHA matrix may change the pharmacokinetics of matrine in the rat significantly. The PBPK model is a valuable tool to gain insights into the disposition kinetics of a botanical drug. DOI
21. Wang, Y; Zhang, ZQ; Garbow, JR; Rowland, DJ; Lubet, RA; Sit, D; Law, F; You, M. (2009) Chemoprevention of Lung Squamous Cell Carcinoma in Mice by a Mixture of Chinese Herbs.Cancer Prevention Research 2: 634-640 Chemoprevention of Lung Squamous Cell Carcinoma in Mice by a Mixture of Chinese Herbs
RANDOMIZED-TRIAL; BETA-CAROTENE; VITAMIN-A; CANCER; MODELS; EFFICACY; MATRINE
Antitumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers. We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (magnetic resonance imaging and computed tomography). ATB decreased lung SCC significantly (3.1-fold; P<0.05) and increased lung hyperplastic lesions by 2.4-fold (P<0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung. These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung SCCs. DOI
20. Jiang Xiaofei, Francis C.P.Law, Qiao Yanjiang, Zou Jiali, Yuan Yuemei, Yao Meicun. (2008) A Preliminary Study: Biotransformation of Borneol to Camphor in Mice, Rats and Rabbits.World Science and Technology/Modernization of Traditional Chinese Medicine and Materia Medica 10(3):27~36 [Chinese Journal]. A Preliminary Study: Biotransformation of Borneol to Camphor in Mice, Rats and Rabbits.
18. Bi, HC; Law, FCP; Zhong, GP; Xu, CS; Pan, Y; Ding, L; Chen, X; Zhao, LZ; Xu, Q; Huang, M. (2007) Study of tanshinone IIA tissue distribution in rat by liquid chromatography-tandem mass spectrometry method.Biomedical Chromatography 21: 473-479 Study of tanshinone IIA tissue distribution in rat by liquid chromatography-tandem mass spectrometry method
tanshinone IIA; tissue distribution; liquid chromatography/tandem mass spectrometry (LC/MS/MS)
A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for determining tanshinone IIA in rat tissues. After a single step liquid-liquid extraction with diethyl ether, tanshinone IIA and loratadine (internal standard) was subjected to LC/MS/MS analysis using positive electro-spray ionization under selected reaction monitoring mode. Chromatographic separation of tanshinone IIA and loratadine was achieved on a Hypersil BDS C-18 column (i.d. 2.1 x 50 mm, 5 mu m) with a mobile phase consisting of methanol-1% formic acid (90:10, v/v) at a flow rate of 300 mu L/min. The intra-day and inter-day precision of the method were less than 10.2 and 12.4%, respectively. The intra-day and inter-day accuracies ranged from 99.7 to 109.7%. The lowest limit of quantification for tanshinone IIA was 1 ng/mL. The method was applied to a tanshinone IIA tissue distribution study after an oral dose of 60 mg/kg to rats. Tanshinone IIA tissue concentrations decreased in the order of stomach > small intestine > lung > liver > fat > muscle > kidneys > spleen > heart > plasma > brain testes. Tanshinone IIA still could be detected in most of the tissues at 20 h post-dosing. These results indicate that the LC/MS/MS method was rapid and sensitive to quantify tanshinone IIA in different rat tissues. Copyright (c) 2007 John Wiley & Sons, Ltd. DOI
16. Nelson, J; Bishay, F; van Roodselaar, A; Ikonomou, M; Law, FCP. (2007) The use of in vitro bioassays to quantify endocrine disrupting chemicals in municipal wastewater treatment plant effluents.Science of the Total Environment 374: 80-90 The use of in vitro bioassays to quantify endocrine disrupting chemicals in municipal wastewater treatment plant effluents
MCF-7; YES; endocrine; wastewater; treatment
In vitro bioassays are widely used to detect and quantify endocrine disrupting chemicals (EDCs) in the influents and effluents of municipal wastewater treatment plants (WWTP). These assays have sometimes led to false positive or negative results, partly due to the low EDC concentrations in the samples. The objectives of the present study were: (a) to compare the estrogen screen (E-Screen) and the yeast estrogen screen (YES) bioassays using the 17 beta-estradiol (E2) or its equivalence and (b) to investigate if a combination of the E-Screen and YES assays can be used to improve the accuracy of EDC detection and quantification. The E-Screen bioassay was conducted with the MCF-7 (BOS) human breast cancer cell line while the YES bioassay employed two different types of recombinant yeast. The influent and effluent samples collected from the five WWTPs operated by the Greater Vancouver Regional District (GVRD) were analyzed by both the E-Screen and the YES bioassays. Since the results of the E-Screen and YES bioassays varied by up to 4-fold on the same split sample of a nominal E2 concentration, the mean value of the E-screen and YES bioassays was used to represent the EDC activity of a given WWTP sample. Results of these studies showed that the E2 equivalent concentration in each WWTP sample was consistently higher than 1 ng/L, a concentration that may potentially cause endocrine disruption in different aquatic species. The composition of selected EDCs in a subset of effluent samples was examined using a gas chromatograph-high resolution mass spectrometer (GC-HRMS). EDC composition in 10 WWTP samples correlated with the mean endocrine disrupting activities of the E-Screen and YES bioassays. Results also indicated that secondary treatment plants are comparable to the primary treatment plants in removing EDCs from the final effluents. (c) 2006 Elsevier B.V. All rights reserved. DOI
15. Li, PCH; Gao, GH; Law, FCP. (2004) Capillary electrophoretic method for determination of matrine in Caco-2 cell medium.J. Liq. Chromatogr. Relat. Technol. 27: 2861-2870 Capillary electrophoretic method for determination of matrine in Caco-2 cell medium
capillary electrophoresis; matrine; Caco-2 cell
A capillary electrophoretic (CE) method has been developed for the analysis of matrine in a biological medium. The optimized run buffer solution contained 200 mM tris(hydroxymethyl)aminomethane, 40 mM sodium dihydrogen phosphate, and 20% 2-propanol, adjusted to pH 5.8 using phosphoric acid. A voltage of 25 kV was applied across a capillary (50 mum x 40 cm, distance to detector: 10.2 cm) for CE separation. Each analysis was completed in less than 5 min. Linearity of matrine calibration in the concentration range of 3.2-185 mug/mL (at the detection wavelength of 214 nm) was excellent (R-2=0.9994). The run-to-run repeatability (n=3), as expressed by the relative standard deviation (RSD), was found to be better than 4.0%. The limit of detection was estimated to be 3.2 mug/mL. This CE method was employed to determine matrine in Caco-2 cell media after transport of matrine through the cells. DOI
14. Sit, DST; Gao, GH; Law, FCP; Li, PCH. (2004) Gas chromatography-mass spectrometry determination of matrine in human plasma.J. Chromatogr. B 808: 209-214 Gas chromatography-mass spectrometry determination of matrine in human plasma
matrine
A method was developed for the quantification of matrine in human plasma using a liquid-liquid extraction procedure followed by gas-chromatography-mass spectrometry (GC/MS) analysis. Deuterated matrine, an internal standard of the analysis, was spiked into the plasma samples before extraction. Linear detection responses were obtained for matrine concentrations ranging from 10 to 500 ng/ml. The intra-day and inter-day precision ranged from 0.4 to 4.0% and 1.0-3.5%, respectively. The intra-day accuracy was between -7.3 and 4.5%. The limit of quantification for matrine was 23 ng/ml. The extraction efficiency averaged about 38%. The validated GC/MS method will be used to quantify matrine in human plasma samples collected in a clinical trial study. (C) 2004 Elsevier B.V. All fights reserved. DOI PubMed
13. Eickhoff, CV; Gobas, FAPC; Law, FCP. (2003) Screening pyrene metabolites in the hemolymph of dungeness crabs (Cancer magister) with synchronous fluorescence spectrometry: Method development and application.Environmental Toxicology and Chemistry 22: 59-66 Screening pyrene metabolites in the hemolymph of dungeness crabs (Cancer magister) with synchronous fluorescence spectrometry: Method development and application
dungeness crab; polycyclic aromatic hydrocarbons; synchronous fluorescence spectrometry biomonitoring
The present study examined the metabolic pathways of pyrene in dungeness crabs (Cancer magister) in the laboratory and the potential of using synchronous fluorescence spectrometry (SFS) to determine pyrene metabolite concentrations in the hemolymph of crabs exposed to polycyclic aromatic hydrocarbons (PAHs) in the field. Pyrene was metabolized by crabs mainly to 1-hydroxypyrene and pyrene-1-glucoside. Both pyrene metabolites could be detected by SFS in the hemolymph of crabs. A nondestructive hemolymph collection procedure was developed and used in conjunction with the SFS assay to assess the exposure of crabs to PAHs in Kitimat Arm (British Columbia, Canada). Our results showed that crabs obtained near the source of PAH contamination had the highest level of pyrene-related fluorescence in the hemolymph, whereas concentrations were lower at other sites downstream from the pollution source. In a separate study, the hepatopancreases of crabs were analyzed for parent PAHs by using gas chromatography-mass spectrometry. Pyrene-associated fluorescent responses of the hemolymph were found to correlate positively with the concentration of total PAHs in the hepatopancreas (r = 0.39, p < 0.05).
12. Eickhoff, CV; He, SX; Gobas, FAPC; Law, FCP. (2003) Determination of polycyclic aromatic hydrocarbons in dungeness crabs (Cancer magister) near an aluminum smelter in Kitimat Arm, British Columbia, Canada.Environmental Toxicology and Chemistry 22: 50-58 Determination of polycyclic aromatic hydrocarbons in dungeness crabs (Cancer magister) near an aluminum smelter in Kitimat Arm, British Columbia, Canada
dungeness crab; Cancer magister; polycyclic aromatic hydrocarbons; biomonitoring; Kitimat, British Columbia, Canada
An aluminum smelter situated at the head of Kitimat Arm (BC, Canada) has discharged polycyclic aromatic hydrocarbons (PAHs) into the receiving waters since 1954. The purpose of the present study was to examine the distribution of PAHs contaminants in dungeness crabs (Cancer magister) collected in Kitimat Arm and Douglas Channel (BC, Canada) by determining the concentrations of PAHs in the hepatopancreas and muscle tissues of crabs by using gas chromatography-mass spectrometry. Crabs were collected at specific sites down the Arm from the smelter on four separate occasions over a three-year period. Hepatopanereas and muscle tissues of the crabs were analyzed for 10 of the 16 PAH priority pollutants recommended by the U.S. Environmental Protection Agency. Results of the studies showed that the crabs had detectable levels of PAHs in hepatopancreas and muscle tissues. The highest concentrations of PAHs in the tissues were found at a site near the aluminum smelter, the alleged point source of PAH discharge. The concentrations of PAH analytes were high in crabs collected close to the smelter and at lower levels in crabs collected throughout Douglas Channel. These results show that PAHS discharged by the smelter were bioavailable to the crabs. The concentration of each PAH analyte in the hepatopanereas was found to be strongly related to its water solubility. However, the PAH analyte concentrations in the hepatopancreas and muscle did not appear to correlate highly with each other.
11. Namdari, R; Abedini, S; Law, FCP. (1999) A comparative tissue distribution study of oxytetracycline in rainbow trout, Oncorhynchus mykiss (Walbaum), and chinook salmon, Oncorhynchus tshawytscha (Walbaum).Aquaculture Research 30: 279-286 A comparative tissue distribution study of oxytetracycline in rainbow trout, Oncorhynchus mykiss (Walbaum), and chinook salmon, Oncorhynchus tshawytscha (Walbaum)
Oxytetracycline (OTC), a broad-spectrum antibiotic, is used widely to treat bacterial diseases in farmed fish. In the present study, the time course of OTC concentrations in freshwater rainbow trout, Oncorhynchus mykiss (Walbaum), and seawater chinook salmon, Oncorhynchus tshawytscha (Walbaum), were compared, tissue by tissue, after receiving a bolus dose of the antibiotic (5 mg kg(-1) or 50 mg kg(-1)) intraarterially (i.a.). The OTC concentration-time profiles of rainbow trout tissues were found to be very similar to those of the corresponding tissues in chinook salmon. Therefore, neither water salinity nor fish species seemed to play an important role in the disposition and elimination of OTC in these salmonids. In a separate experiment, rainbow trout were implanted surgically with a urinary cannula and received a single dose of OTC (50 mg kg(-1)) i.a. Urine was collected from the cannula daily for 13 days. The amount of OTC excreted into the bile was found to be larger than that eliminated by the urine. These results show the similarity of OTC pharmacokinetics in freshwater rainbow trout and seawater chinook salmon and render support in using a single fish species to study the pharmacokinetics of a drug for other species in the same taxon.
10. Abedini, S; Namdari, R; Law, FCP. (1998) Comparative pharmacokinetics and bioavailability of oxytetracycline in rainbow trout and chinook salmon.Aquaculture 162: 23-32 Comparative pharmacokinetics and bioavailability of oxytetracycline in rainbow trout and chinook salmon
pharmacokinetics; bioavailability; oxytetracycline; chinook salmon; rainbow trout
The pharmacokinetics and bioavailabilities of oxytetracycline (OTC) in seawater chinook salmon (Oncorhynchus tshawytscha) and freshwater rainbow trout (Oncorhynchus mykiss) were compared after they were given a single dose of OTC (50 mg/kg) via the i.a. or per os route of administration at 11 degrees C water. At specific time points post-dosing, blood Samples were withdrawn from the fish, extracted by a solid phase extractor and analyzed for OTC with a high performance liquid chromatograph (HPLC). Similar OTC blood concentration-time profiles were found in trout and salmon after they were treated by the same administration route with OTC. A two- and a three-compartment open pharmacokinetic models, respectively, were used to describe the pharmacokinetics of OTC following the per os and i.a. routes of administration. The model-derived pharmacokinetic parameters and the apparent bioavailabilities of OTC also were remarkably similar: the elimination half-life, volume of distribution and oral bioavailability of OTC in chinook salmon were 88.29 h, 0.89 l/kg and 24.84%, respectively; the corresponding values for rainbow trout were 94.22 h, 0.87 l/kg and 30.30%, respectively. Results of the present studies indicate that species difference and salinity as high as 24 parts per thousand do not play an important role in the absorption and elimination of OTC by the salmonids. Moreover, freshwater trout may be used as a model salmonid to study OTC pharmacokinetics in seawater salmon and vice versa. (C) 1998 Elsevier Science B.V.
7. Haddad, S; Withey, J; Lapare, S; Law, FCP; Krishnan, K. (1998) Physiologically-based pharmacokinetic modeling of pyrene in the rat.Environmental Toxicology and Pharmacology 5: 245-255 Physiologically-based pharmacokinetic modeling of pyrene in the rat
pyrene; physiological pharmacokinetics; pharmacokinetic modeling; PBPK modeling
The objective of the present study was to develop a physiologically-based model to simulate the oral and i.v. pharmacokinetics of pyrene in the rat. The physiologically-based pharmacokinetic (PBPK) model for pyrene consisted of the following tissue compartments: liver, lungs, adipose tissue, slowly perfused tissues, and richly perfused tissues interconnected with arterial and venous blood pools. The tissue:blood partition coefficients required for the pyrene PBPK model were estimated by equilibrium dialysis. Using perfusion-limited descriptions for tissue uptake and previously determined in vitro-derived hepatic metabolism rate constants (V-max and K-m), the PBPK model predicted a faster clearance of pyrene than that suggested by the experimental data. The biological basis of PBPK model then provided an opportunity to refine the estimate of V-max, and to explore and uncover additional mechanistic determinants of pyrene disposition in vivo. Accordingly, the in vitro V-max had to be lowered by about a factor of 10 to adequately simulate experimental data on pyrene pharmacokinetics. Further, the model simulations could be matched with the experimental data on tissue concentrations of pyrene only with the considerations of (i) diffusion-limited uptake in slowly perfused tissues and adipose tissue, and (ii) binding to proteins in metabolizing tissues (lungs and liver). The present study successfully integrated the available data on oral and i.v, pharmacokinetics of pyrene using a physiological model framework, and identified several mechanistic data gaps that should be addressed by future research efforts. (C) 1998 Elsevier Science B.V. All rights reserved.
6. He, SX; Nicholson, RA; Law, FCP. (1998) Benzo(a)pyrene toxicokinetics in the cricket following injection into the haemolymph.Environmental Toxicology and Pharmacology 6: 81-89 Benzo(a)pyrene toxicokinetics in the cricket following injection into the haemolymph
toxicokinetics; benzo(a)pyrene; tissue distribution; metabolism; cricket
The metabolic disposition of C-14-labelled benzo(a)pyrene (BP) ire the cricket (Acheta domesticus) was investigated after injection into the haemolymph. C-14-BP was taken up rapidly by the nerve cord, malpighian tubules, reproductive organs, gut, and muscle:cuticle of the cricket. The elimination half-lives of C-14-BP in these tissues ranged from 8.9 to 17.8 h. The haemolymph C-14-BP concentration-time curve could be described by a one-compartment open pharmacokinetic model. C-14-BP was metabolized by the cricket mainly to unconjugated and conjugated BP metabolites since very little unchanged C-14-BP was found in the excreta at 48 h post-dosing. GLPC-MSD and HPLC/ES-MS analyses showed the presence of at least two BP metabolites in the excreta. The BP metabolites were identified tenatively as the diol derivatives of benzo(a)pyrene and benzo(a)pyrene quinone. (C) 1998 Elsevier Science B.V. All rights reserved.
4. Grudzinski, IP; Law, FCP. (1997) Nitrite mediated T lymphocyte responses in the intestinal immune system of mice infected with Trichinella spiralis nematode.Archives of Environmental Contamination and Toxicology 32: 462-466 Nitrite mediated T lymphocyte responses in the intestinal immune system of mice infected with Trichinella spiralis nematode
The effects of orally administered sodium nitrite (20 mg NaNO2/kg b.w) on the responses of T and B lymphocytes collected from the mesenteric lymph nodes were studied in resistant AKR/J, H-2(k) haplotype mice infected with Trichinella spiralis nematode, On days 6, 9, and 12 postinfection, the mesenteric lymph node cells (MLNC) were collected from the mice and assayed for lymphocyte subsets (CD4(+), CD8(+), B220(+)), cytokines (IL-2, IL-5), and INF-gamma. At the same time, the number of adult worms in the small intestine were counted. Infection of the nitrite-treated mice with T. spiralis L1 larvae caused a marked increase in the number of adult worms in the small intestine, However, preincubation of T. spiralis L1 larvae with nitrite before Infecting the mice resulted in a significant reduction in the number of adult worms (p < 0.05), Preincubation of T. spiralis L1 larvae with nitrite also caused an increase in the number of CD4(+) and CD8(+) cells as well as IL-2, IL-5, and INF-gamma levels. An increased level of CD8(+) subsets and a depression of IL-2 and IL-5 production by MLNC were observed in mice infected with larvae without nitrite pretreatment. Since supplementary rIL-1 alpha was found to alter INF-gamma secretion by MLNC in vitro, the pattern of MLNC proliferation was examined further with the nitrite-treated mice. Sodium nitrite increased thymidine incorporation into the MLNC. However, INF-gamma production was not enhanced when rIL-1 alpha was added to The MLNC culture obtained from nitrite-treated mice.
3.Law, FCP; Meng, J. (1996) Binding of C-14-furazolidone metabolites to the muscular and hepatic proteins of trout.Food Additives and Contaminants 13: 199-209 Binding of C-14-furazolidone metabolites to the muscular and hepatic proteins of trout
furazolidone metabolites; covalent binding; trout
A high level of C-14 was found to bind irreversibly with the liver proteins of rainbow trout (Oncorhyncus mykiss) exposed to 135 mg/kg bodyweight of C-14-labelled furazolidone (C-14-FZ) in fish feed daily for 10 days. After the cessation of C-14-FZ treatment, hepatic protein-bound C-14 in trout stayed high for at least 30 days. The chemical identity of protein-bound C-14 remained to be elucidated. However, a part of the protein-bound C-14 in the liver and muscle could be released as 3-amino-2-oxazolidinone by acid hydrolysis. The formation of protein-bound C-14 in the liver was investigated further with trout dosed intravenously with different C-14-FZ doses at 10 degrees C or with 5 mg/kg FZ at different water temperatures. C-14 binding to the liver proteins was found to increase with increasing FZ dose or water temperature. Results of these studies indicate that protein-bound C-14 in the muscle and liver of trout is related to the formation of reactive intermediates from FZ. However, additional studies on the identities of the protein-bound FZ residues are required before they can serve as useful biomarkers to monitor FZ exposure in farm fish.
2. Namdari, R; Abedini, S; Law, FCP. (1996) Tissue distribution and elimination of oxytetracycline in seawater chinook and coho salmon following medicated-feed treatment.Aquaculture 144: 27-38 Tissue distribution and elimination of oxytetracycline in seawater chinook and coho salmon following medicated-feed treatment
chinook salmon; coho salmon; medicated feed; oxytetracycline
The time course of oxytetracycline (OTC) tissue residues were studied in two different species of the pacific salmon: the chinook salmon (Oncorhynchus tshawytscha) and the coho salmon (Oncorhynchus kisutch). The chinook salmon were treated with OTC-medicated feed at the rate of 75 mg OTC kg(-1) body weight per day for 21 days in 9 degrees C or 15 degrees C seawater. The coho salmon were treated at the rate of 100 mg OTC kg(-1) body weight per day for 42 days in 10 degrees C seawater. Non-medicated diet was offered to the salmon at the conclusion of the OTC treatment period. The salmon were medicated by OTC for a prolonged period to establish the maximal OTC withdrawal time. At different times during and after OTC medication, five or six salmon were randomly selected from the tank and killed. The tissues of the salmon were analyzed for OTC by high-performance liquid chromatography (HPLC). The tissue distribution profiles of OTC in both species of the pacific salmon were found to be very similar, OTC tissue concentration decreased in the order liver > bone > kidney = skin > muscle at the conclusion of the OTC treatment period. However, OTC tissue concentrations in the chinook salmon were about twice as high as those of the coho salmon. OTC elimination from different tissues of salmon treated under similar experimental conditions could be described by a single temperature-dependent elimination rate constant. Our results also show that OTC concentrations in the muscle of chinook salmon fell below the HPLC detection limit of 0.05 mu g g(-1) at Day 41 and Day 65 post-dosing when the acclimation temperatures were 15 degrees C and 9 degrees C, respectively. These results confirm the current Canadian guidelines on OTC withdrawal time for farmed salmon.
1. Namdari, R; Law, FCP. (1996) Toxicokinetics of waterborne pyrene in rainbow trout (Oncorhynchus mykiss) following branchial or dermal exposure.Aquatic Toxicology 35: 221-235 Toxicokinetics of waterborne pyrene in rainbow trout (Oncorhynchus mykiss) following branchial or dermal exposure
toxicokinetics pyrene; rainbow trout; free-swimming exposure; chambered exposure; dermal absorption
The uptake and depuration of waterborne pyrene were studied in rainbow trout (Oncorhynchus mykiss) implanted with a dorsal aortic cannula. The trout were placed individually either in an exposure chamber (chamber-restrained mode) or in a 30-1 glass aquarium (free-swimming mode) and exposed to water containing 8 mg l(-1) pyrene for 4 h at 12+/-2 degrees C. The exposure chamber could be divided by a latex diaphragm into the front and the rear subcompartments and used to study either the branchial or the dermal uptake of waterborne pyrene by trout. After pyrene exposure, the trout were provided with uncontaminated water to study the depuration of pyrene. Blood samples were withdrawn through the cannula at specific time intervals during and after pyrene exposure. The blood samples were extracted by hexane and analyzed for pyrene by HPLC. Pyrene concentrations in the blood of trout after branchial exposure were significantly higher than those of the dermally exposed trout indicating the gills as the most important route of waterborne pyrene absorption. Our results also showed that the chamber-restrained trout had a significantly larger area under the blood concentration-time curve than the free-swimming trout although both groups of fish had been exposed to 8 mg l(-1) of waterborne pyrene. Since an exposure chamber may enhance the systemic absorption of waterborne pyrene by the trout, care must be exercised in extrapolating results from the chamber-restrained trout to the free-swimming trout.
