Development of a Physiologically Based Pharmacokinetics (PBPK) Model to Probe Naphthalene Toxicity in a Micro CCA

แบบจำลองเชิงกายภาพด้านจลนเภสัชศาสตร์เพื่อวิเคราะห์ความเป็นพิษของแนฟทาลีนในเครื่องมือซีซีเอ

Name: Utsanee Chamkate

Organization : King Mongkut's University of Technology Thonburi. Faculty of Engineering. Chemical Engineering

Name: Utsanee Chamkate

Organization : King Mongkut's University of Technology Thonburi. Faculty of Engineering. Chemical Engineering

keyword: Naphthalene Toxicity

; PBPK Model

; ไมโครซีซีเอ

; ความเป็นพิษของ naphthalene

Abstract: A physiologically based pharmacokinetic (PBPK) model has been developed to determine the metabolism, and biological response of humans to various chemicals and drugs. Our goal is to develop a physiologically based pharmacokinetics (PBPK) model to predict the naphthalene toxicity in a four-chamber (“lung”, “liver”, “fat”, “other tissue”) microscale cell culture analog (uCCA) device. This model has been developed from in vitro data for naphthalene toxicity. The lung and liver compartments contain cell culture to mimic the key functions in actual organs. In addition, each chamber is connected via a circulating cell culture medium that acts as blood surrogate. Naphthalene and its primary metabolites are metabolized by enzymes in lung and liver cells. Furthermore, the nonenzymatic reactions of naphthalene metabolites in the cell culture and the medium are included in the model. The kinetic constants for the model were derived from primary cell culture data presented in the literature. Some kinetic parameters, particularly for naphthalene oxide and napthoquinone conjugate with glutathione, were previously estimated from curve-fitting and needed to be optimized. In this study, the original codes from FORTRAN were ported to MATLAB. Some of the kinetic parameters were optimized to reflect the current experimental setting. Overall, the model predictions are in good agreement with most of the experimental results. In the toxicity study using L2 and C3A cells, it is evident that the model is unable to describe the re-synthesis of GSH in the liver cells, leading to a large error in the prediction. More studies are needed to determine the kinetic parameters involved in this mechanism. The results indicated that C3A cells have approximately 15 times higher enzyme activity than H4IIE cells. Moreover, the model suggests that the toxic metabolites in naphthalene toxicity are naphthalene oxide and naphthoquinone. These two metabolites cause cell damage by conjugating with GSH and decreasing the level of GSH available in the cells.

King Mongkut's University of Technology Thonburi

Address: BANGKOK

Email: info.lib@mail.kmutt.ac.th

Name: Kwanchanok Viravaidya

Role: Advisor

Name: Hong-ming Ku

Role: Advisor

Name: ขวัญชนก วีระไวทยะ

Role: อาจารย์ที่ปรึกษา

Created: 2006

Modified: 2552-03-06

Issued: 2009-03-06

วิทยานิพนธ์/Thesis

application/pdf

CallNumber: CHE1762

eng

DegreeName: Master of Engineering

Level: Master's Degree

Descipline: Chemical Engineering

Grantor: King Mongkut's University of Technology Thonburi

©copyrights King Mongkut's University of Technology Thonburi

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