Journal Article

Dose-Response Modeling of Cytochrome P450 Induction in Rats by Octamethylcyclotetrasiloxane

Ramesh Sarangapani, Justin Teeguarden, Kathleen P. Plotzke, James M. McKim and Melvin E. Andersen

in Toxicological Sciences

Volume 67, issue 2, pages 159-172
Published in print June 2002 | ISSN: 1096-6080
Published online June 2002 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/67.2.159
Dose-Response Modeling of Cytochrome P450 Induction in Rats by Octamethylcyclotetrasiloxane

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Inhalation of octamethylcyclotetrasiloxane (D4) induces CYP2B1/2 protein and causes liver enlargement. We have developed a pharmacodynamic (PD) extension to a physiologically based pharmacokinetic (PBPK) model to characterize these dose-response behaviors. The PD model simulates interactions of D4 with a putative receptor, leading to increased production of cytochrome P450 2B1/2. Induction was modeled with a Hill equation with dissociation constant, Kd, and Hill coefficient, N. Both a 1- and a 5-compartment liver model were evaluated. The PBPK model provided excellent simulations of tissue D4 and hepatic CYP2B1/2 protein concentrations following 6 h/day, 5-day inhalation exposures to 0, 1, 7, 30, 70, 150, 300, 500, 700, or 900 ppm D4. Either the 1- or 5-compartment liver model could accurately simulate increases in CYP2B1/2 protein in the liver. With a 1-compartment liver, Kd and N were 0.67 μM (free liver concentration) and 1.9, respectively. The 5-compartment model used higher N-values (∼ 4.0) and varied Kd between compartments. The fitted 5-compartment model parameters were Kd = 0.67 μM in the midzonal compartment with geometric differences in Kd between compartments of 2.9. On the basis of unbound (free) plasma concentrations, D4 appeared to be a higher potency inducer than phenobarbital (PB). Dose-response curves for increased liver weights had N |mS 1.0 and Kd |mS 3.4 μM, very different values from those for enzyme induction. Exposure concentration leading to a 0.1% increase in CYP2B1/2 protein predicted by the 1- and 5-compartment models were 2.1 ppm and 5.1 ppm, respectively. The 1- and 5-compartment liver models provided very similar fits to the whole liver induction data, excluding the lowest dose, but the 5-compartment liver model had the additional advantage of simultaneously describing the regional induction of CYP2B1/2.

Keywords: siloxane; pharmacodynamic; enzyme induction; inhalation; modeling

Journal Article.  10812 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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