Methamphetamine-induced changes in the activities of
drug-metabolizing enzymes:

D 2006

Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies

HADAŠOVÁ, Eva, Veronika MINAŘÍKOVÁ, Miroslav DOSTÁLEK, Lucia ZAHRADNÍKOVÁ, Jan JUŘICA et. al.

Basic information

Original name

Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies

Name in Czech

Změny v aktivitě metabolizujících enzymů vyvolané metamfetaminem: korelační studie "in vivo" . in vitro"

Authors

HADAŠOVÁ, Eva, Veronika MINAŘÍKOVÁ, Miroslav DOSTÁLEK, Lucia ZAHRADNÍKOVÁ and Jan JUŘICA

Edition

první. Cagliari, Itálie, Monitoring Molecules in Neuroscience, p. 415-417, 3 pp. 2006

Publisher

University of Cagliari

Other information

Language

English

Type of outcome

Stať ve sborníku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Italy

Confidentiality degree

není předmětem státního či obchodního tajemství

Organization unit

Faculty of Medicine

Keywords in English

methamphetamine; drug metabolism; pharmacokinetics; liver perfusion; rat;

Abstract

ORIG CZ

V originále

The aim of the present study was to ascertain the influence of MET on activities of rat isoforms of CYP enzymes, mainly of CYP2C, CYP2D and CYP3A. In order to comprise the complexity of the possible pharmacokinetic changes evoked by methamphetamine, several series of experiments on various models and levels were performed in Wistar rats treated with MET: 1) the pharmacokinetic study in vivo; 2) the study on the isolated perfused rat liver; 3) the study on the rat liver microsomes. The results obtained in the isolated perfused rat liver confirmed the stimulatory effect of MET treatment on the CYP2D enzyme subfamily as it was observed in the in vivo experiments; AUC of dextromethorphan was significantly decreased (p<0.001) but Cl of dextromethorphan was significantly increased. Concurrently, the AUC of the O-demethylated metabolite dextrorphan was markedly increased (p<0.001). Furthermore, there was demonstrated a highly significant stimulation of CYP2C6 (p<0.001) in the isolated perfused liver when tolbutamid was used as a selective substrate. On the other hand, the experiments in the isolated liver did not confirm the stimulatory effect of MET on CYP3A subfamily as it could be suggested on the base of the in vivo pharmacokinetic experiments. the study performed in the liver microsomes supplied the detailed view about the direct effects of the in vivo pretreatment of rats with MET on the specific microsomal enzymes. Out of the monooxygenases tested, i.e. ethylresorufin-O-deethylase (EROD, CYP1A1/2), pentylresorufin-O-deethylase (PROD, CYP2B), ethoxycoumarin-O-deethylase (ECOD, CYP2A), erythromycine-N-demethylase (ERDM, CYP3A), 4-nitrophenol hydroxylase (NPH, CYP2E1) and dextromethorphan-O-demethylase (DXDM, CYP2D6), only CYP2D showed an insignificant stimulation and CYP2E1 was markedly inhibited.

In Czech

Cílem studie bylo objasnit vliv metamfetaminu na aktivitu potkaních izoforem CYP enzymů.

Links

MSM0021622404, plan (intention)

Name: Vnitřní organizace a neurobiologické mechanismy funkčních systémů CNS

Investor: Ministry of Education, Youth and Sports of the CR, The internal organisation and neurobiological mechanisms of functional CNS systems under normal and pathological conditions.

Citovat

HADAŠOVÁ, Eva, Veronika MINAŘÍKOVÁ, Miroslav DOSTÁLEK, Lucia ZAHRADNÍKOVÁ and Jan JUŘICA. Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies. In Monitoring Molecules in Neuroscience. první. Cagliari, Itálie: University of Cagliari, 2006, p. 415-417.

@inproceedings{705103,
   author = {Hadašová, Eva and Minaříková, Veronika and Dostálek, Miroslav and Zahradníková, Lucia and Juřica, Jan},
   address = {Cagliari, Itálie},
   booktitle = {Monitoring Molecules in Neuroscience},
   edition = {první},
   keywords = {methamphetamine; drug metabolism; pharmacokinetics; liver perfusion; rat;},
   language = {eng},
   location = {Cagliari, Itálie},
   pages = {415-417},
   publisher = {University of Cagliari},
   title = {Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies},
   year = {2006}
}

TY  - JOUR
ID  - 705103
AU  - Hadašová, Eva - Minaříková, Veronika - Dostálek, Miroslav - Zahradníková, Lucia - Juřica, Jan
PY  - 2006
TI  - Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies
PB  - University of Cagliari
CY  - Cagliari, Itálie
KW  - methamphetamine
KW  - drug metabolism
KW  - pharmacokinetics
KW  - liver perfusion
KW  - rat;
N2  - The aim of the present study was to ascertain the influence of MET on activities of rat isoforms of CYP enzymes, mainly of CYP2C, CYP2D and CYP3A. In order to comprise the complexity of the possible pharmacokinetic changes evoked by methamphetamine, several series of experiments on various models and levels were performed in Wistar rats treated with MET: 1) the pharmacokinetic study in vivo; 2) the study on the isolated perfused rat liver; 3) the study on the rat liver microsomes. The results obtained in the isolated perfused rat liver confirmed the stimulatory effect of MET treatment on the CYP2D enzyme subfamily as it was observed in the in vivo experiments; AUC of dextromethorphan was significantly decreased (p<0.001) but Cl of dextromethorphan was significantly increased. Concurrently, the AUC of the O-demethylated metabolite dextrorphan was markedly increased (p<0.001). Furthermore, there was demonstrated a highly significant stimulation of CYP2C6 (p<0.001) in the isolated perfused liver when tolbutamid was used as a selective substrate. On the other hand, the experiments in the isolated liver did not confirm the stimulatory effect of MET on CYP3A subfamily as it could be suggested on the base of the in vivo pharmacokinetic experiments. the study performed in the liver microsomes supplied the detailed view about the direct effects of the in vivo pretreatment of rats with MET on the specific microsomal enzymes. Out of the monooxygenases tested, i.e. ethylresorufin-O-deethylase (EROD, CYP1A1/2), pentylresorufin-O-deethylase (PROD, CYP2B), ethoxycoumarin-O-deethylase (ECOD, CYP2A), erythromycine-N-demethylase (ERDM, CYP3A), 4-nitrophenol hydroxylase (NPH, CYP2E1) and dextromethorphan-O-demethylase (DXDM, CYP2D6), only CYP2D showed an insignificant stimulation and CYP2E1 was markedly inhibited.
ER  -

HADAŠOVÁ, Eva, Veronika MINAŘÍKOVÁ, Miroslav DOSTÁLEK, Lucia ZAHRADNÍKOVÁ and Jan JUŘICA. Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: ''in vivo - in vitro'' correlation studies. In \textit{Monitoring Molecules in Neuroscience}. první. Cagliari, Itálie: University of Cagliari, 2006, p.~415-417.

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