Dose-response modeling of cytochrome p450 induction in rats by octamethylcyclotetrasiloxane.
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 microM (free liver concentration) and 1.9, respectively. The 5-compartment model used higher N-values (approximately 4.0) and varied Kd between compartments. The fitted 5-compartment model parameters were Kd = 0.67 microM 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 microM, 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.
Sarangapani
Ramesh
R
The K.S. Crump Group, ICF Consulting, P.O. Box 14348, Research Triangle Park, NC 27709, USA.
Teeguarden
Justin
J
Plotzke
Kathleen P
KP
McKim
James M
JM
Andersen
Melvin E
ME
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000280:Administration, Inhalation; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1 / Q000032:analysis / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D051381:Rats; D012833:Siloxanes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D013250:Steroid Hydroxylases / Q000032:analysis / Q000096:biosynthesis*
D000276:Adjuvants, Immunologic; D012833:Siloxanes; D003577:Cytochrome P-450 Enzyme System; C024064:octamethylcyclotetrasiloxane; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase