Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data

Dofetilide, a class III antidysrhythmic agent, undergoes both renal and metabolic clearance. Characterization of the metabolism in vitro allows explanation of species differences, whereas identification of the human enzymes involved permits assessment of potential drug interaction. In liver microsom...

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Published in:	Drug metabolism and disposition Vol. 24; no. 4; p. 447
Main Authors:	Walker, D K, Alabaster, C T, Congrave, G S, Hargreaves, M B, Hyland, R, Jones, B C, Reed, L J, Smith, D A
Format:	Journal Article
Language:	English
Published:	United States 01-04-1996
Subjects:	Action Potentials - drug effects Animals Anti-Arrhythmia Agents - metabolism Anti-Arrhythmia Agents - pharmacokinetics Anti-Arrhythmia Agents - pharmacology Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Dogs Drug Interactions Enzyme Inhibitors - pharmacology Female Guinea Pigs Heart - drug effects Hemodynamics - drug effects Humans In Vitro Techniques Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Male Microsomes, Liver - drug effects Microsomes, Liver - metabolism Papillary Muscles - drug effects Phenethylamines - metabolism Phenethylamines - pharmacokinetics Phenethylamines - pharmacology Rats Sulfonamides - metabolism Sulfonamides - pharmacokinetics Sulfonamides - pharmacology
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Summary:	Dofetilide, a class III antidysrhythmic agent, undergoes both renal and metabolic clearance. Characterization of the metabolism in vitro allows explanation of species differences, whereas identification of the human enzymes involved permits assessment of potential drug interaction. In liver microsomes, the rate of oxidative metabolism of dofetilide is in the order: male rat > female rat > dog > humans, which correlates with the metabolic clearance seen in vivo. In vitro products of oxidative metabolism, formed by N-dealkylation, are the same as those formed in vivo, with the N-desmethyl being the major product. This route of dofetilide metabolism is mediated by cytochrome P450 (CYP). In humans, N-demethylation has a high KM of 657 +/- 116 microM, indicating low affinity for the enzyme's active site. In a number of human liver microsomal preparations, this rate correlated (r = 0.903) with the activity of CYP3A4. There was no correlation with the activities of other isozymes. Specific isozyme inhibitors also indicated the involvement of CYP3A4, with partial inhibition being observed with ketoconazole and troleandeomycin, whereas the activator, alpha-naphthaflavone, caused increased turnover. No inhibition was observed with specific inhibitors or competing substrates for other isozymes. Dofetilide did not significantly inhibit CYP2C9, CYP2D6, or CYP3A4 at concentrations up to 100 microM in vitro. In contrast, amiodarone (IC50, 25 microM) and flecainide (49 microM) inhibited CYP2C9 and quinidine (0.26 microM), and flecainide (0.44 microM) inhibited CYP2D6. Many antidysrhythmic drugs have active, circulating metabolites, complicating the relationship of dose and clinical response. In vitro pharmacology studies allow assessment of the potential contribution to the pharmacological profile by metabolites. Potency of dofetilide and metabolites has been compared for class III (K+ channel blockade) and class I (Na+ channel blockade) antidysrhythmic activities. Three of the metabolites of dofetilide displayed class III activity, but at concentrations at least 20-fold higher than dofetilide. Dofetilide N-oxide showed class I activity, but only at high concentration. Neither resting membrane potential or action potential amplitude were affected by any metabolite. This lack of biologically relevant activity is in accord with the close correlation between plasma concentrations of dofetilide and pharmacological response.
ISSN:	0090-9556