Abstract
Cytochromes P450 (P450, CYP) are a superfamily of enzymes that participate
especially in the oxidative metabolism of various xenobiotics and endogenous
compounds.
The major goal of this study was to characterise suitable methods for routine
preclinical in vitro testing of new chemical entities (NCE)
and to test the methods for the affinity screening of selected drugs.
In vitro methods used involve the utilisation of human
liver microsomes for studies with P450-selective reference inhibitors,
inhibitory antibodies and cDNA-expressed enzymes in cytochrome P450-catalysed
activities and for studying the reactions of selegiline and entacapone.
In this project, the CYP-catalysed oxidative in vitro
biotransformation of selegiline into its primary metabolites desmethylselegiline
and l-methamphetamine and the transformation of entacapone
into its in vitro metabolite
N-desethylentacapone were studied. The affinities of
selegiline, desmethylselegiline, l-methamphetamine,
entacapone, candesartan, eprosartan, irbesartan, losartan and valsartan to P450
enzymes were also elucidated, and the selectivity of tranylcypromine as a
CYP2A6-selective reference inhibitor was characterised.
The most important findings were that the methodology developed during this work
is suitable for preclinical in vitro testing of NCEs and
that the results obtained for the studied compounds are in line with the
available in vivo data.
By the in vitro testing methodology, it is possible to
target the in vivo interaction studies to the relevant
groups of compounds. The in vitro methods presented in this
thesis could also make the early phases of drug development more cost-effective.
Further, the number of animals used for in vivo testing in
preclinical metabolism and interaction studies can be markedly reduced by
effectively using this methodology.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5900-9 |
| Date | 13 February 2001 |
| Creators | Taavitsainen, P. (Päivi) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2001 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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