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In vitro evaluation of potentialin vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms.
- Source :
-
British Journal of Clinical Pharmacology . Oct2000, Vol. 50 Issue 4, p311. 4p. - Publication Year :
- 2000
-
Abstract
- Aims To determine the FMO and P450 isoform selectivity for metabolism of benzydamine and caffeine, two potential in vivo probes for human FMO. Methods Metabolic incubations were conducted at physiological pH using substrate concentrations of 0.01-10 mM with either recombinant human FMOs, P450s or human liver microsomes serving as the enzyme source. Products of caffeine and benzydamine metabolism were analysed by reversed-phase h.p.l.c, with u.v. and fluorescence detection. Results CYP1A2, but none of the human FMOs, catalysed metabolism of caffeine. In contrast, benzydamine was a substrate for human FMO1, FMO3, FMO4 and FMO5. Apparent K[sub m] values for benzydamine N-oxygenation were 60±8 μM, 80±8 μM, >3 mM and >2 mM, for FMO1, FMO3, FMO4 and FMO5, respectively. The corresponding V[sub max] values were 46±2 min[sup -1], 36±2 min[sup -1], -75 min[sup -1] and <1 min[sup minus;1]. Small quantities of benzydamine N-oxide were also formed by CYPs 1A1, 1A2, 2C19, 2D6 and 3A4. Conclusions FMO1 and FMO3 catalyse benzydamine N-oxygenation with the highest efficiency. However, it is likely that the metabolic capacity of hepatic FMO3 is a much greater contributor to plasma levels of the N-oxide metabolite in vivo than is extrahepatic FMO1. Therefore, benzydamine, but not caffeine, is a potential in vivo probe for human FMO3. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MONOOXYGENASES
*CAFFEINE
*CYTOCHROME P-450
*MICROSOMES
*FLAVINS
Subjects
Details
- Language :
- English
- ISSN :
- 03065251
- Volume :
- 50
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- British Journal of Clinical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 5637763
- Full Text :
- https://doi.org/10.1046/j.1365-2125.2000.00265.x