Prediction of in vivo metabolic clearance of 25 different petroleum hydrocarbons by a rat liver head-space technique

Mortensen, Bjarte; Eide, Ingvar; Zahlsen, Kolbjørn; Nilsen, Odd G.

doi:10.1007/s002040000135

Cited by 9 publications

(14 citation statements)

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“…The PCs and metabolic constants required to develop Note: a The experimental values of partition coefficients were obtained from Gargas et al [8] and Smith et al [10]. Experimental values of CL int are from Mortensen et al [12]. chemical-specific PBPK models are most often obtained from in vivo or in vitro studies (reviewed by Krishnan and Andersen [4]).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro data on maximal velocity (V max ) and Michaelis-Menten constant (K m ) for 20 C 5 -C 10 VOCs determined using rat liver slices with the vial equilibrium technique were obtained from Mortensen et al [12]. After the calculation of intrinsic clearance (CL int ¼ V max /K m ), these values were used for developing QSPRs.…”

Section: Qspr For CL Intmentioning

confidence: 99%

“…The closed chamber (or gas uptake) method and the exhaled breath chamber method are two non-invasive in vivo methods which have been used for the estimation of metabolism rate constants of VOCs [4,11]. Subcellular fractions, post-mitochondrial preparations, isolated cells, tissue slices and isolated perfused organs are all potentially useful as in vitro systems for the estimation of metabolic rate constants for PBPK modelling [4,12]. Given that experimental determination of physicochemical and metabolic parameters for a variety of chemicals could be time and resource intensive, there is an increasing interest in developing biologically-based algorithms and quantitative structure-activity relationships (QSARs) to predict these parameters.…”

Section: Introductionmentioning

confidence: 99%

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An integrated QSPR–PBPK modelling approach for in vitro–in vivo extrapolation of pharmacokinetics in rats

Kamgang

Peyret

Krishnan

2008

SAR and QSAR in Environmental Research

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In vitro data on metabolism and partitioning may be integrated within physiologically-based pharmacokinetic (PBPK) models to provide simulations of the kinetics and bioaccumulation of chemicals in intact organisms. Quantitative structure-property relationship (QSPR) modelling of available in vitro data may be performed to predict metabolism rates and partition coefficients (PCs) for developing in vivo PBPK models. The objective of the present study was to develop an integrated QSPR-PBPK modelling approach for the conduct of in vitro to in vivo extrapolation. For this purpose, data on rat blood:air (P(b)) and fat:air (P(f)) PCs, as well as intrinsic metabolic clearance (CL(int)) obtained using rat liver slices for some C(5)-C(10) volatile organic compounds (VOCs) were compiled from the literature. Multilinear additive QSPR models for P(f), P(b) and CL(int) were developed based on the number and nature of molecular fragments in these VOCs (CH(3), CH(2), CH, C, C=C, H, benzene ring and H in benzene ring structure). The mean estimated/experimental (est/exp) ratios (+/-SD; range) were 1.0 (+/-0.04; 0.93 - 1.06) for log P(f), 1.08 (+/-0.26; 0.70 - 1.62) for log P(b), and 1.07 (+/- 0.21; 0.80 - 1.44) for CL(int). By accounting for the difference in the content of neutral lipids in fat and other tissues, the liver : air and muscle : air PCs of the compounds investigated in this study, with the excerption of n-decane, were adequately predicted from P(f). Integrating the QSPRs for P(f), P(b) and CL(int) within a rat PBPK model, simulations of inhalation pharmacokinetics of several VOCs were generated on the basis of molecular structure, for a given exposure scenario. The integrated QSPR-PBPK model developed in this study is a potentially useful tool for predicting in vivo kinetics and bioaccumulation of chemicals in rats under poor data situations.

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Section: Discussionmentioning

confidence: 99%

Section: Qspr For CL Intmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An integrated QSPR–PBPK modelling approach for in vitro–in vivo extrapolation of pharmacokinetics in rats

Kamgang

Peyret

Krishnan

2008

SAR and QSAR in Environmental Research

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“…Michaelis-Menten metabolic constants for n-decane have been measured (Km = 1.5 mg/L and Vmax = 0.4 mg/h) using rat liver slices in a vial headspace equilibration system (Mortensen et al, 2000). These data indicate that clearance via liver metabolism is minimal for n-alkanes, which, in addition to their lipophilicity, contributes to their tendency toward increased body retention.…”

Section: Model Parameterizationmentioning

confidence: 99%

Improved Predictive Model forn-Decane Kinetics Across Species, as a Component of Hydrocarbon Mixtures

Merrill

Gearhart

Sterner

et al. 2008

Inhalation Toxicology

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n-Decane is considered a major component of various fuels and industrial solvents. These hydrocarbon products are complex mixtures of hundreds of components, including straight-chain alkanes, branched chain alkanes, cycloalkanes, diaromatics, and naphthalenes. Human exposures to the jet fuel, JP-8, or to industrial solvents in vapor, aerosol, and liquid forms all have the potential to produce health effects, including immune suppression and/or neurological deficits. A physiologically based pharmacokinetic (PBPK) model has previously been developed for ndecane, in which partition coefficients (PC), fitted to 4-h exposure kinetic data, were used in preference to measured values. The greatest discrepancy between fitted and measured values was for fat, where PC values were changed from 250-328 (measured) to 25 (fitted). Such a large change in a critical parameter, without any physiological basis, greatly impedes the model's extrapolative abilities, as well as its applicability for assessing the interactions of n-decane or similar alkanes with other compounds in a mixture model. Due to these limitations, the model was revised. Our approach emphasized the use of experimentally determined PCs because many tissues had not approached steady-state concentrations by the end of the 4-h exposures. Diffusion limitation was used to describe n-decane kinetics for the brain, perirenal fat, skin, and liver. Flow limitation was used to describe the remaining rapidly and slowly perfused tissues. As expected from the high lipophilicity of this semivolatile compound (log K ow = 5.25), sensitivity analyses showed that parameters describing fat uptake were next to blood:air partitioning and pulmonary ventilation as critical in determining overall systemic circulation and uptake in other tissues. In our revised model, partitioning into fat took multiple days to reach steady state, which differed considerably from the previous model that assumed steady-state conditions in fat at 4 h post dosing with 1200 ppm. Due to these improvements, and particularly the reconciliation between measured and fitted partition coefficients, especially fat, we have greater confidence in using the proposed model for dose, species, and route of exposure extrapolations and as a harmonized model approach for other hydrocarbon components of mixtures.Hydrocarbon mixtures are complex and include straightchain alkanes, branched and cyloalkanes, diaromatics, and naphthalenes. JP-8 jet fuel, for example, generally contains about 18% aromatic hydrocarbons, and the rest is aliphatic hydrocarbons (1996). In order to develop mechanistic tools capable of predicting dose-response from human exposures to jet fuel, it is necessary to provide links between kinetic models and mechanisms of action, together with a framework for additional interaction. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models represent a means of integrating diverse data sets in a mechanism-based analysis. The approach proposed here is to initially develop single-chemical PBPK models...

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“…Die Ab bau ra te hö he rer ali pha ti scher KW nimmt mit an stei gen der Koh len stoff zahl ab [26]. …”

Section: Me Ta Bo Lis Mus Und Aus Schei Dungunclassified

Richtwerte für die Innenraumluft: Aromatenarme Kohlenwasserstoffgemische (C9–C14)

Sagunski

Mangelsdorf

2005

Bundesgesundheitsbl - Gesundheitsforsch - Gesundheitsschutz

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To protect public health the German Joint Working Group on Indoor Guidelines of the Federal Environmental Protection Agency and the States' Departments of Health is issuing indoor air guideline values based on a fixed procedure published in 1996. Regarding dearomatized hydrocarbon solvents/white spirits (DAWS--CAS-No. 64742-47-8, 64742-48-9, 64742-88-7, 64741- 65-7) no human data are available. From animal studies, neurotoxicity, developmental toxicity and reproductive toxicity were identified as critical endpoints. For risk evaluation the Hass et al. (2001) study was used as the pivotal study. Based on effects at 4680 mg DAWS/m(3) for the endpoint developmental toxicity, the lowest adverse effect level for chronic exposure is assessed as 400 mg DAWS/m(3). By applying an interspecies factor of 10, an intraspecies factor of 10 and an additional factor 2 referring to the special physiology of children (higher breath rate compared to adults) a so-called health hazard value of 2 mg DAWS/m(3) indoor air and a so-called health prevention value of 0.2 mg DAWS/m(3) are obtained.

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Prediction of in vivo metabolic clearance of 25 different petroleum hydrocarbons by a rat liver head-space technique

Cited by 9 publications

References 0 publications

An integrated QSPR–PBPK modelling approach for in vitro–in vivo extrapolation of pharmacokinetics in rats

An integrated QSPR–PBPK modelling approach for in vitro–in vivo extrapolation of pharmacokinetics in rats

Improved Predictive Model forn-Decane Kinetics Across Species, as a Component of Hydrocarbon Mixtures

Richtwerte für die Innenraumluft: Aromatenarme Kohlenwasserstoffgemische (C9–C14)

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