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Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene.
Toxicol Appl Pharmacol. 2006 Jul 01; 214(1):78-87.TA

Abstract

The objective of the present study was to evaluate the magnitude of interindividual variability in the internal dose of toluene in children of various age groups, on the basis of subject-specific hepatic CYP2E1 content and physiology. The methodology involved the use of a previously validated physiologically based pharmacokinetic (PBPK) model, in which the intrinsic clearance for hepatic metabolism (CL(int)) was expressed in terms of the CYP2E1 content. The adult toluene PBPK model, with enzyme content-normalized CL(int), facilitated the calculation of child-specific CL(int) based on knowledge of hepatic CYP2E1 protein levels. The child-specific physiological parameters, except liver volume, were computed with knowledge of age and body weight, whereas physicochemical parameters for toluene were kept age-invariant based on available data. The actual individual-specific liver volume (autopsy data) was also included in the model. The resulting model was used to simulate the blood concentration profiles in children exposed by inhalation, to 1 ppm toluene for 24 h. For this exposure scenario, the area under the venous blood concentration vs. time curve (AUC) ranged from 0.30 to 1.01 microg/ml x h in neonates with low CYP2E1 concentration (<3.69 pmol/mg protein). The simulations indicated that neonates with higher levels of CYP2E1 (4.33 to 55.93 pmol/mg protein) as well as older children would have lower AUC (0.16 to 0.43 microg/ml x h). The latter values were closer to those simulated for adults. Similar results were also obtained for 7 h exposure to 17 ppm toluene, a scenario previously evaluated in human volunteers. The interindividual variability factor for each subgroup of children and adults, calculated as the ratio of the 95th and 50th percentile values of AUC, was within a factor of 2. The 95th percentile value of the low metabolizing neonate group, however, was greater than the mean adult AUC by a factor of 3.9. This study demonstrates the feasibility of incorporating subject-specific data on hepatic CYP2E1 content and physiology within PBPK models for evaluating the age, interchild and population variability of internal dose for use in risk assessment of inhaled volatile organics.

Authors+Show Affiliations

Occupational and Environmental Health, Université de Montréal, Montreal, QC, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16464483

Citation

Nong, A, et al. "Modeling Interchild Differences in Pharmacokinetics On the Basis of Subject-specific Data On Physiology and Hepatic CYP2E1 Levels: a Case Study With Toluene." Toxicology and Applied Pharmacology, vol. 214, no. 1, 2006, pp. 78-87.
Nong A, McCarver DG, Hines RN, et al. Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. Toxicol Appl Pharmacol. 2006;214(1):78-87.
Nong, A., McCarver, D. G., Hines, R. N., & Krishnan, K. (2006). Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. Toxicology and Applied Pharmacology, 214(1), 78-87.
Nong A, et al. Modeling Interchild Differences in Pharmacokinetics On the Basis of Subject-specific Data On Physiology and Hepatic CYP2E1 Levels: a Case Study With Toluene. Toxicol Appl Pharmacol. 2006 Jul 1;214(1):78-87. PubMed PMID: 16464483.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. AU - Nong,A, AU - McCarver,D G, AU - Hines,R N, AU - Krishnan,K, Y1 - 2006/02/07/ PY - 2005/06/28/received PY - 2005/12/05/revised PY - 2005/12/05/accepted PY - 2006/2/9/pubmed PY - 2006/8/12/medline PY - 2006/2/9/entrez SP - 78 EP - 87 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 214 IS - 1 N2 - The objective of the present study was to evaluate the magnitude of interindividual variability in the internal dose of toluene in children of various age groups, on the basis of subject-specific hepatic CYP2E1 content and physiology. The methodology involved the use of a previously validated physiologically based pharmacokinetic (PBPK) model, in which the intrinsic clearance for hepatic metabolism (CL(int)) was expressed in terms of the CYP2E1 content. The adult toluene PBPK model, with enzyme content-normalized CL(int), facilitated the calculation of child-specific CL(int) based on knowledge of hepatic CYP2E1 protein levels. The child-specific physiological parameters, except liver volume, were computed with knowledge of age and body weight, whereas physicochemical parameters for toluene were kept age-invariant based on available data. The actual individual-specific liver volume (autopsy data) was also included in the model. The resulting model was used to simulate the blood concentration profiles in children exposed by inhalation, to 1 ppm toluene for 24 h. For this exposure scenario, the area under the venous blood concentration vs. time curve (AUC) ranged from 0.30 to 1.01 microg/ml x h in neonates with low CYP2E1 concentration (<3.69 pmol/mg protein). The simulations indicated that neonates with higher levels of CYP2E1 (4.33 to 55.93 pmol/mg protein) as well as older children would have lower AUC (0.16 to 0.43 microg/ml x h). The latter values were closer to those simulated for adults. Similar results were also obtained for 7 h exposure to 17 ppm toluene, a scenario previously evaluated in human volunteers. The interindividual variability factor for each subgroup of children and adults, calculated as the ratio of the 95th and 50th percentile values of AUC, was within a factor of 2. The 95th percentile value of the low metabolizing neonate group, however, was greater than the mean adult AUC by a factor of 3.9. This study demonstrates the feasibility of incorporating subject-specific data on hepatic CYP2E1 content and physiology within PBPK models for evaluating the age, interchild and population variability of internal dose for use in risk assessment of inhaled volatile organics. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/16464483/Modeling_interchild_differences_in_pharmacokinetics_on_the_basis_of_subject_specific_data_on_physiology_and_hepatic_CYP2E1_levels:_a_case_study_with_toluene_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(05)00669-1 DB - PRIME DP - Unbound Medicine ER -