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Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat.
Res Commun Chem Pathol Pharmacol. 1983 Jun; 40(3):391-403.RC

Abstract

Product inhibition is thought to be involved in unexpected accumulation of orphenadrine, which occurs during chronic medication with this anti-Parkinson drug in man. In previous studies (Biochem. Pharmacol. 31, 2745-2753 (1982) we established the formation of reactive metabolic intermediates (MI) during metabolism of orphenadrine and its mono-N-demethylated metabolite tofenacine, which may block cytochrome P-450 (MI-complex). In this study we investigated the role of MI-complexation in product inhibition. Three different assays were used to establish the amount of cytochrome P-450 involved in MI-complexation, which was induced by tofenacine (30 mg/kg i.p.) in phenobarbital pretreated rats. If liver microsomes were prepared 3 hours after tofenacine injection, both spectral titration of oxidized cytochrome P-450, determination of loss of metyrapone binding sites at reduced cytochrome P-450 as well as ferricyanide oxidation of the MI-complex revealed 8-13% complexation of cytochrome P-450. Our data also suggest that MI-complexation is generated on phenobarbital induced cytochrome P-450 species. Phenobarbital induction was also shown to activate orphenadrine metabolism in vitro. Moreover, with a newly developed capillary GLC method, using nitrogen detection, we showed inhibition of orphenadrine- and tofenacine metabolism in vitro, by MI-complexation. This study therefore showed that MI-complexation may produce product inhibition.

Authors

Bast A
No affiliation info available
van Kemenade FA
No affiliation info available
Savenije-Chapel EM
No affiliation info available
Noordhoek J
No affiliation info available

MeSH

AnimalsCytochrome P-450 Enzyme SystemIn Vitro TechniquesMaleMicrosomes, LiverOrphenadrinePhenobarbitalRatsRats, Inbred Strains

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

6622816

Citation

Bast, A, et al. "Product Inhibition in Orphenadrine Metabolism as a Result of a Stable Cytochrome P-450-metabolic Intermediate Complex Formed During the Disposition of mono-N-desmethylorphenadrine (tofenacine) in the Rat." Research Communications in Chemical Pathology and Pharmacology, vol. 40, no. 3, 1983, pp. 391-403.
Bast A, van Kemenade FA, Savenije-Chapel EM, et al. Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat. Res Commun Chem Pathol Pharmacol. 1983;40(3):391-403.
Bast, A., van Kemenade, F. A., Savenije-Chapel, E. M., & Noordhoek, J. (1983). Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat. Research Communications in Chemical Pathology and Pharmacology, 40(3), 391-403.
Bast A, et al. Product Inhibition in Orphenadrine Metabolism as a Result of a Stable Cytochrome P-450-metabolic Intermediate Complex Formed During the Disposition of mono-N-desmethylorphenadrine (tofenacine) in the Rat. Res Commun Chem Pathol Pharmacol. 1983;40(3):391-403. PubMed PMID: 6622816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat. AU - Bast,A, AU - van Kemenade,F A, AU - Savenije-Chapel,E M, AU - Noordhoek,J, PY - 1983/6/1/pubmed PY - 1983/6/1/medline PY - 1983/6/1/entrez SP - 391 EP - 403 JF - Research communications in chemical pathology and pharmacology JO - Res Commun Chem Pathol Pharmacol VL - 40 IS - 3 N2 - Product inhibition is thought to be involved in unexpected accumulation of orphenadrine, which occurs during chronic medication with this anti-Parkinson drug in man. In previous studies (Biochem. Pharmacol. 31, 2745-2753 (1982) we established the formation of reactive metabolic intermediates (MI) during metabolism of orphenadrine and its mono-N-demethylated metabolite tofenacine, which may block cytochrome P-450 (MI-complex). In this study we investigated the role of MI-complexation in product inhibition. Three different assays were used to establish the amount of cytochrome P-450 involved in MI-complexation, which was induced by tofenacine (30 mg/kg i.p.) in phenobarbital pretreated rats. If liver microsomes were prepared 3 hours after tofenacine injection, both spectral titration of oxidized cytochrome P-450, determination of loss of metyrapone binding sites at reduced cytochrome P-450 as well as ferricyanide oxidation of the MI-complex revealed 8-13% complexation of cytochrome P-450. Our data also suggest that MI-complexation is generated on phenobarbital induced cytochrome P-450 species. Phenobarbital induction was also shown to activate orphenadrine metabolism in vitro. Moreover, with a newly developed capillary GLC method, using nitrogen detection, we showed inhibition of orphenadrine- and tofenacine metabolism in vitro, by MI-complexation. This study therefore showed that MI-complexation may produce product inhibition. SN - 0034-5164 UR - https://www.unboundmedicine.com/medline/citation/6622816/Product_inhibition_in_orphenadrine_metabolism_as_a_result_of_a_stable_cytochrome_P_450_metabolic_intermediate_complex_formed_during_the_disposition_of_mono_N_desmethylorphenadrine__tofenacine__in_the_rat_ DB - PRIME DP - Unbound Medicine ER -
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