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


CONCLUSIONS
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.
Magnusson
Mats O
MO
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24, Uppsala, Sweden. Mats.Magnusson@farmbio.uu.se
Karlsson
Mats O
MO
Sandström
Rikard
R
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003580:Cytochromes; D004790:Enzyme Induction; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008954:Models, Biological; D010634:Phenobarbital / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D003580:Cytochromes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C017170:Cyp1a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010634:Phenobarbital