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Inhibition of thiabendazole metabolism in the rat
Abstract:
1. A single oral dose of desmethylimipramine (80 mg/kg) administered to rats inhibited the hepatic microsomal hydroxylation of thiabendazole (45%), aniline (30%), biphenyl (30%) and ethylmorphine (15%) in vitro at 5 h after dosage; there was no decrease in cytochrome P-450 or b5. 2. A single oral dose of ethoxyquin (200 mg/kg) to rats inhibited the hepatic microsomal hydroxylation of thiabendazole (65%), aniline (40%) and biphenyl (40%) in vitro at 1 h after dosage; inhibition was less at 5 h. There were no changes in the contents of cytochromes P-450 and b5. 3. The max. plasma concn. of thiabendazole occurred 2--4 h after oral dosing (50--200 mg/kg) to rats. Thiabendazole (100 mg/kg) administered orally 30 min after oral ethoxyquin (400 mg/kg) or thiabendazole (200 mg/kg) administered orally 30 min after oral desmethylimipramine (80 mg/kg) delayed absorption of the thiabendazole and resulted in markedly markedly decreased plasma concentration of the anthelmintic. 4. Simultaneous administration of ethoxyquin (300 mg/kg) potentiated the anthelmintic effect of thiabendazole (750 mg/kg) on the helminth parasite, Nematospiroides dubius, in the mouse. Desmethylimipramine showed no similar potentiation.
Insights
Desmethylimipramine and ethoxyquin inhibit drug metabolism in rats, affecting thiabendazole absorption and efficacy. Ethoxyquin potentiated thiabendazole
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Drug interactions can significantly alter therapeutic outcomes.
- Understanding the impact of co-administered substances on drug metabolism is crucial for effective treatment.
- Hepatic microsomal enzymes play a key role in xenobiotic metabolism.
Purpose of the Study:
- To investigate the effects of desmethylimipramine and ethoxyquin on the metabolism and absorption of thiabendazole in rats.
- To evaluate the impact of these agents on hepatic microsomal hydroxylation pathways.
- To determine if co-administration influences the anthelmintic efficacy of thiabendazole.
Main Methods:
- Administration of desmethylimipramine and ethoxyquin to rats via oral dosage.
- In vitro assessment of hepatic microsomal hydroxylation of various substrates (thiabendazole, aniline, biphenyl, ethylmorphine).
- Measurement of plasma concentrations of thiabendazole following co-administration with desmethylimipramine or ethoxyquin.
- Evaluation of the anthelmintic effect of thiabendazole in mice challenged with Nematospiroides dubius.
Main Results:
- Desmethylimipramine and ethoxyquin inhibited hepatic microsomal hydroxylation of thiabendazole, aniline, and biphenyl in rats.
- Co-administration of ethoxyquin or desmethylimipramine with thiabendazole delayed thiabendazole absorption and reduced its plasma concentration.
- Ethoxyquin, but not desmethylimipramine, potentiated the anthelmintic effect of thiabendazole against Nematospiroides dubius in mice.
Conclusions:
- Desmethylimipramine and ethoxyquin are inhibitors of hepatic drug-metabolizing enzymes.
- These agents can significantly alter the pharmacokinetic profile and reduce the absorption of concurrently administered thiabendazole.
- Ethoxyquin demonstrates potential for enhancing the therapeutic efficacy of thiabendazole through drug interaction.