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A Mechanism-Based Integrated Pharmacokinetic Enzyme Model Describing the Time Course and Magnitude of Phenobarbital-Mediated Enzyme Induction in the Rat

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Purpose

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.

Methods

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.

Results

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.

Conclusion

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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Abbreviations

CYP:

cytochrome P450

EROD:

etoxyresorufin

i.p.:

intraperitoneal

k out :

turnover rate constant

OHT:

hydroxytestosterone

PB:

phenobarbital

PK:

pharmacokinetics

R in :

production rate

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Acknowledgments

We are grateful to Britt Jansson for assistance in the laboratory and to Kjell Wikvall and Siv Jönsson for valuable comments on the work.

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Authors and Affiliations

  1. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24, Uppsala, Sweden

    Mats O. Magnusson, Mats O. Karlsson & Rikard Sandström

Authors
  1. Mats O. Magnusson
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  2. Mats O. Karlsson
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  3. Rikard Sandström
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Correspondence to Mats O. Magnusson.

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Magnusson, M.O., Karlsson, M.O. & Sandström, R. A Mechanism-Based Integrated Pharmacokinetic Enzyme Model Describing the Time Course and Magnitude of Phenobarbital-Mediated Enzyme Induction in the Rat. Pharm Res 23, 521–532 (2006). https://doi.org/10.1007/s11095-005-9571-z

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