uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
A mechanistic model describing the impact of carbamazepine on the pharmacokinetics of clomethiazole and its metabolite NLA-715
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Show others and affiliations
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-95738OAI: oai:DiVA.org:uu-95738DiVA: diva2:170064
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2011-03-01
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 52
Pharmacokinetics/Pharmacotherapy, Pharmacokinetics, Pharmacodynamics, Enzyme induction, Time course, Turnover model, Mechanism-based, Modelling, NONMEM, Farmakokinetik/Farmakoterapi
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
Available from: 2007-04-13 Created: 2007-04-13Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Division of Pharmacokinetics and Drug Therapy

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 145 hits
ReferencesLink to record
Permanent link

Direct link