A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat

Pharmaceutical Research
Mats O MagnussonRikard Sandström

Abstract

To characterize the magnitude, time course, and specificity of phenobarbital (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB. PB plasma concentrations and in vitro activities of several CYP enzymes were measured in rats treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: . PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for CYP1A2, CYP3A1/2, and CYP2B1/2, and 3 days for androstenedione producing enzymes. The CYP2C11 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities. To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.

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Citations

Sep 24, 2013·Biochemical Pharmacology·Jianghong Fan, Inés A M de Lannoy
Oct 4, 2014·British Journal of Clinical Pharmacology·Elisabet StørsetChristine E Staatz
Sep 7, 2014·The Veterinary Journal·V ZancanellaM Dacasto
Oct 12, 2014·Regulatory Toxicology and Pharmacology : RTP·H TinwellR Bars
Feb 19, 2013·Biochemical Pharmacology·Christoffer BundgaardJohn P Redrobe
Jan 6, 2011·The Journal of Pharmacology and Experimental Therapeutics·Joseph J RaybonSean Kim

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