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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2006 (English)In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 23, no 3, 521-532 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2006. Vol. 23, no 3, 521-532 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95739DOI: 10.1007/s11095-005-9571-zPubMedID: 16525862OAI: oai:DiVA.org:uu-95739DiVA: diva2:170065
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pharmacodynamics of Enzyme Induction and its Consequences for Substrate Elimination
Open this publication in new window or tab >>Pharmacodynamics of Enzyme Induction and its Consequences for Substrate Elimination
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Enzyme induction is a process whereby a molecule enhances the expression of enzymes. If the affected enzymes are involved in the elimination of a drug, this may result in a drug interaction. Induction is therefore of major concern during drug development and in clinical practice.

The induction process depends on the half-life of the induced enzyme, the pharmacokinetics of the inducing agent, and the relationship between the inducer’s concentration and the induction stimulus. The aim of the conducted research was to investigate these key aspects of enzyme induction and the consequences that induction has for substrate elimination.

Successful investigations of the induction process presuppose the existence of appropriate methods for the estimation of the metabolic activity. Enzyme activity measurements can be conducted in tissues with low enzyme content using the analytical method presented here.

A model was developed describing the changes in the pharmacokinetics of clomethiazole and its metabolite NLA-715, that are attributable to carbamazepine induction. The consequences of the induction was explained using a mechanistic approach, acknowledging food-induced changes in the blood flow to the liver, and interpreting in vitro generated metabolic information.

The time course of the induction process was examined in two investigations. In the first of these, the pharmacokinetics of the autoinducing drug phenobarbital and its effect on several enzymes were described in rats. This was accomplished by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner. In the final investigation, the time course of the increase and cessation in enzyme activity was studied in healthy volunteers treated with carbamazepine. This investigation allowed the half-lives of CYP3A and CYP1A2 to be estimated.

The key aspects of the enzyme induction process have been examined using mechanistic induction models. These novel models improve the understanding of the induction process and its consequences for substrate elimination.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 52
Keyword
Pharmacokinetics/Pharmacotherapy, Pharmacokinetics, Pharmacodynamics, Enzyme induction, Time course, Turnover model, Mechanism-based, Modelling, NONMEM, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-7812 (URN)978-91-554-6860-6 (ISBN)
Public defence
2007-05-04, B:41, BMC, Uppsala, Sweden, 13:15
Opponent
Supervisors
Available from: 2007-04-13 Created: 2007-04-13Bibliographically approved

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Karlsson, Mats O.

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