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In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole.
Drug Metab Dispos. 1997 Jul; 25(7):840-4.DM

Abstract

The in vitro metabolism of ropinirole was investigated with the aim of identifying the cytochrome P450 enzymes responsible for its biotransformation. The pathways of metabolism after incubation of ropinirole with human liver microsomes were N-despropylation and hydroxylation. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to each pathway. A high affinity component with a K(M) of 5-87 microM and a low affinity component with a K(M) of approximately two orders of magnitude greater were evident. The high affinity component could be abolished by pre-incubation of the microsomes with furafylline. Additionally, incubation of ropinirole with microsomes derived from CYP1A2 transfected cells readily produced the N-despropyl and hydroxy metabolites. Some inhibition of ropinirole metabolism was also observed with ketoconazole, indicating a minor contribution by CYP3A. Multivariate correlation data were consistent with the involvement of the cytochrome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it could be concluded that the major P450 enzyme responsible for ropinirole metabolism at lower (clinically relevant) concentrations is CYP1A2 with a contribution from CYP3A, particularly at higher concentrations.

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Authors+Show Affiliations

Bloomer JC
Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, UK.
Clarke SE
No affiliation info available
Chenery RJ
No affiliation info available

MeSH

BiotransformationCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDealkylationDopamine AgonistsEnzyme InhibitorsHumansHydroxylationIn Vitro TechniquesIndolesIsoenzymesMicrosomes, LiverMultivariate Analysis

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9224778

Citation

Bloomer, J C., et al. "In Vitro Identification of the P450 Enzymes Responsible for the Metabolism of Ropinirole." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 25, no. 7, 1997, pp. 840-4.
Bloomer JC, Clarke SE, Chenery RJ. In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole. Drug Metab Dispos. 1997;25(7):840-4.
Bloomer, J. C., Clarke, S. E., & Chenery, R. J. (1997). In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 25(7), 840-4.
Bloomer JC, Clarke SE, Chenery RJ. In Vitro Identification of the P450 Enzymes Responsible for the Metabolism of Ropinirole. Drug Metab Dispos. 1997;25(7):840-4. PubMed PMID: 9224778.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole. AU - Bloomer,J C, AU - Clarke,S E, AU - Chenery,R J, PY - 1997/7/1/pubmed PY - 1997/7/1/medline PY - 1997/7/1/entrez SP - 840 EP - 4 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 25 IS - 7 N2 - The in vitro metabolism of ropinirole was investigated with the aim of identifying the cytochrome P450 enzymes responsible for its biotransformation. The pathways of metabolism after incubation of ropinirole with human liver microsomes were N-despropylation and hydroxylation. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to each pathway. A high affinity component with a K(M) of 5-87 microM and a low affinity component with a K(M) of approximately two orders of magnitude greater were evident. The high affinity component could be abolished by pre-incubation of the microsomes with furafylline. Additionally, incubation of ropinirole with microsomes derived from CYP1A2 transfected cells readily produced the N-despropyl and hydroxy metabolites. Some inhibition of ropinirole metabolism was also observed with ketoconazole, indicating a minor contribution by CYP3A. Multivariate correlation data were consistent with the involvement of the cytochrome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it could be concluded that the major P450 enzyme responsible for ropinirole metabolism at lower (clinically relevant) concentrations is CYP1A2 with a contribution from CYP3A, particularly at higher concentrations. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/9224778/In_vitro_identification_of_the_P450_enzymes_responsible_for_the_metabolism_of_ropinirole_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9224778 DB - PRIME DP - Unbound Medicine ER -