Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the... more Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,... more A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.
Advances in Experimental Medicine and Biology, 2001
Biotransformation enzymes modify xenobiotic compounds into more hydrophilic products (metabolites... more Biotransformation enzymes modify xenobiotic compounds into more hydrophilic products (metabolites) which can be efficiently excreted from the body. Phase 1 enzymes, of which the cytochromes P450 are the most important, perform functionalization reactions creating a reactive centre in the molecule through oxidation or reduction. Phase 2 enzymes, such as glutathione S-transferases, UDP-glucuronyltransferases, N-acetyltransferases and sulphotransferases couple an endogenous molecule to a functional moiety in the molecule or metabolite from the phase 1 reaction, generally leading to more hydrophilic metabolites that are easily excreted with urine or bile.
Within the framework of in vitro alternatives for in uiuo safety assessment, the kinetic behaviou... more Within the framework of in vitro alternatives for in uiuo safety assessment, the kinetic behaviour of a compound can be described by biokinetic models. These models, with emphasis on the physiologically based pharmacokinetic models, need a variety of biological, physicochemical and biochemical parameters. This paper deals with the possibilities for obtaining these data from in vitro studies. Examples are given for parameters on absorption (both dermal and intestinal), distribution and metabolism.
A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two co... more A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two components of the hydrocarbon solvent mixture white spirit (WS), 1,2,4-trimethylbenzene (TMB) and n-decane (DEC) as markers for the aromatic and aliphatic fractions. The PBPK model was used to simulate brain (target tissue) concentrations of the two compounds in rats, which were well predicted by the model. The rat model was then allometrically scaled up to the human situation. The concentrations of TMB and DEC in blood and expired air predicted by the human model were compared to those measured during and following a 4-hour exposure to WS at 100 ppm. For both compounds, good predictions were made for blood and exhaled air levels. Calculated human brain concentrations were correlated to brain concentration-effect relationships found in the rat. It was estimated that a WS exposure level of ~140 ppm could be expected to results in CNS depressant effects, which is consistent with results of a...
Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the... more Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
Scopolamine MK-801 Aging Time delay SLV330 Cannabinoid CB 1 receptor (CB 1 R) antagonist T-maze C... more Scopolamine MK-801 Aging Time delay SLV330 Cannabinoid CB 1 receptor (CB 1 R) antagonist T-maze Continuous Alternation Task (T-CAT) Object Recognition Task (ORT) Social Recognition Task (SRT) Mice Rats a b s t r a c t Cannabinoid CB 1 receptor (CB 1 R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB 1 R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The ace-tylcholinesterase inhibitor (AChEI) donepezil (Aricept Ò , approved for symptomatic treatment of Alzhei-mer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.). In conclusion, the CB 1 R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability t... more A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the present study it is demonstrated that hepatic GST activity towards these compounds can be elevated significantly in female and male Fischer-344 rats by feeding these animals on diets supplemented with cancer chemopreventive agents. Immunoblotting experiments showed that increased activity towards the dihaloalkanes is associated with elevated levels of the GSTT1 subunit in rat liver. Sex-specific effects were observed in the induction of GSTT1 protein. Amongst the chemopreventive agents tested, indole-3-carbinol proved to be the most potent inducer of hepatic GSTT1 in male rats (6.2-fold), whereas coumarin was the most potent inducer of this su...
A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the... more A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans.
A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,... more A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.
A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two co... more A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two components of the hydrocarbon solvent mixture white spirit (WS), 1,2,4-trimethylbenzene (TMB) and n-decane (DEC) as markers for the aromatic and aliphatic fractions. The PBPK model was used to simulate brain (target tissue) concentrations of the two compounds in rats, which were well predicted by the model. The rat model was then allometrically scaled up to the human situation. The concentrations of TMB and DEC in blood and expired air predicted by the human model were compared to those measured during and following a 4-hour exposure to WS at 100 ppm. For both compounds, good predictions were made for blood and exhaled air levels. Calculated human brain concentrations were correlated to brain concentration-effect relationships found in the rat. It was estimated that a WS exposure level of ~140 ppm could be expected to results in CNS depressant effects, which is consistent with results of a...
Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the... more Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,... more A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.
Advances in Experimental Medicine and Biology, 2001
Biotransformation enzymes modify xenobiotic compounds into more hydrophilic products (metabolites... more Biotransformation enzymes modify xenobiotic compounds into more hydrophilic products (metabolites) which can be efficiently excreted from the body. Phase 1 enzymes, of which the cytochromes P450 are the most important, perform functionalization reactions creating a reactive centre in the molecule through oxidation or reduction. Phase 2 enzymes, such as glutathione S-transferases, UDP-glucuronyltransferases, N-acetyltransferases and sulphotransferases couple an endogenous molecule to a functional moiety in the molecule or metabolite from the phase 1 reaction, generally leading to more hydrophilic metabolites that are easily excreted with urine or bile.
Within the framework of in vitro alternatives for in uiuo safety assessment, the kinetic behaviou... more Within the framework of in vitro alternatives for in uiuo safety assessment, the kinetic behaviour of a compound can be described by biokinetic models. These models, with emphasis on the physiologically based pharmacokinetic models, need a variety of biological, physicochemical and biochemical parameters. This paper deals with the possibilities for obtaining these data from in vitro studies. Examples are given for parameters on absorption (both dermal and intestinal), distribution and metabolism.
A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two co... more A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two components of the hydrocarbon solvent mixture white spirit (WS), 1,2,4-trimethylbenzene (TMB) and n-decane (DEC) as markers for the aromatic and aliphatic fractions. The PBPK model was used to simulate brain (target tissue) concentrations of the two compounds in rats, which were well predicted by the model. The rat model was then allometrically scaled up to the human situation. The concentrations of TMB and DEC in blood and expired air predicted by the human model were compared to those measured during and following a 4-hour exposure to WS at 100 ppm. For both compounds, good predictions were made for blood and exhaled air levels. Calculated human brain concentrations were correlated to brain concentration-effect relationships found in the rat. It was estimated that a WS exposure level of ~140 ppm could be expected to results in CNS depressant effects, which is consistent with results of a...
Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the... more Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
Scopolamine MK-801 Aging Time delay SLV330 Cannabinoid CB 1 receptor (CB 1 R) antagonist T-maze C... more Scopolamine MK-801 Aging Time delay SLV330 Cannabinoid CB 1 receptor (CB 1 R) antagonist T-maze Continuous Alternation Task (T-CAT) Object Recognition Task (ORT) Social Recognition Task (SRT) Mice Rats a b s t r a c t Cannabinoid CB 1 receptor (CB 1 R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB 1 R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The ace-tylcholinesterase inhibitor (AChEI) donepezil (Aricept Ò , approved for symptomatic treatment of Alzhei-mer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.). In conclusion, the CB 1 R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.
A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability t... more A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the present study it is demonstrated that hepatic GST activity towards these compounds can be elevated significantly in female and male Fischer-344 rats by feeding these animals on diets supplemented with cancer chemopreventive agents. Immunoblotting experiments showed that increased activity towards the dihaloalkanes is associated with elevated levels of the GSTT1 subunit in rat liver. Sex-specific effects were observed in the induction of GSTT1 protein. Amongst the chemopreventive agents tested, indole-3-carbinol proved to be the most potent inducer of hepatic GSTT1 in male rats (6.2-fold), whereas coumarin was the most potent inducer of this su...
A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the... more A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans.
A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,... more A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.
A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two co... more A physiologically based pharmacokinetic (PBPK) model for rats and humans was developed for two components of the hydrocarbon solvent mixture white spirit (WS), 1,2,4-trimethylbenzene (TMB) and n-decane (DEC) as markers for the aromatic and aliphatic fractions. The PBPK model was used to simulate brain (target tissue) concentrations of the two compounds in rats, which were well predicted by the model. The rat model was then allometrically scaled up to the human situation. The concentrations of TMB and DEC in blood and expired air predicted by the human model were compared to those measured during and following a 4-hour exposure to WS at 100 ppm. For both compounds, good predictions were made for blood and exhaled air levels. Calculated human brain concentrations were correlated to brain concentration-effect relationships found in the rat. It was estimated that a WS exposure level of ~140 ppm could be expected to results in CNS depressant effects, which is consistent with results of a...
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