Propafenone is mainly metabolized by CYP2D6 to form 5-hydroxypropafenone (5-OHP) and to a minor extent by CYP1A2 and CYP3A4 to form N-depropylpropafenone (N-DPP). The in vitro inhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on the formation of both metabolites was studied, using human liver microsomes. The 5-OHP formation from racemic propafenone and from its individual enantiomers followed one-enzyme Michaelis-Menten kinetics. Incubation with the racemate yielded a mean Vmax of 64 pmol x min(-1) x mg(-1) and a mean Km of 0.12 microM (N = 3). Stereoselectivity in Vmax and Km values was observed, with (S)-propafenone displaying higher Km and Vmax values. N-DPP formation from racemic propafenone followed one-enzyme Michaelis-Menten kinetics and yielded a mean Vmax of 403 pmol x min(-1) x mg(-1) and a mean Km of 116 microM (N = 3). No stereoselectivity in propafenone N-dealkylation was observed. The influence of SSRIs and quinidine, a prototypical CYP2D6 inhbitor, on propafenone 5-hydroxylation was investigated. Quinidine was the most potent inhibitor, followed by fluoxetine, norfluoxetine, and paroxetine. Sertraline, desmethylsertraline, and fluvoxamine had only a moderate inhibitory effect, whereas citalopram displayed slight or no inhibition when racemic propafenone was used as substrate. Mean Ki values of quinidine, fluoxetine, norfluoxetine, and paroxetine were 0.13, 0.33, 0.55, and 0.54 microM, respectively (N = 3). Quinidine and paroxetine were also tested as inhibitors using the individual enantiomers, but no stereoselectivity was observed. Among the SSRIs tested, only fluvoxamine substantially inhbited propafenone N-dealkylation with a mean IC50 of 7.0 microM (N = 3). There was a more pronounced inhibitory effect of fluvoxamine on (R)-propafenone than on (S)-propafenone N-dealkylation. In conclusion, these in vitro data suggest that an in vivo interaction between propafenone and the SSRIs, fluoxetine and paroxetine, can be expected, which can lead to clinically relevant beta-blockade and an increased risk of side effects in the central nervous system. An interaction with fluvoxamine may be of importance in poor metabolizers for CYP2D6.

1. After hydrolysis with glusulase of bile from rats treated with papaverine, four metabolites (A, B, C and D) were separated. 2. The structures A, B and C were established as monodemethylated compounds, 4'-desmethyl-, 7-desmethyl-, and 6-desmethylpapaverine, respectively. 3. D was formed from papaverine by bis-desmethylation. Since it was found in cat bile after administering either A or C, but not B, it was identified as 4', 6-desmethylpapaverine.

Concentrations of antipyrine, phenylbutazone and phenytoin were measured in serum and in tissues of rabbits with acute renal failure after uranyl nitrate injection, in view of our earlier finding that the volume of distribution of phenytoin and of phenylbutazone is increased in those animals. Concentrations of antipyrine in serum and in tissues were not altered in the uraemic rabbit. For phenylbutazone, total serum concentrations were decreased in uraemic rabbits; concentrations in brain, liver and fat were increased, while concentrations in other tissues and unbound serum concentrations were not significantly changed. For phenytoin, total serum concentrations were decreased and unbound serum concentrations and tissue concentrations were not significantly changed in uraemic rabbits. Calculation of the ratios of tissue concentrations over unbound serum concentrations suggests that the increased distribution volume of phenylbutazone and phenytoin in the uraemic rabbit is due to the decreased serum binding rather than to changes in tissue binding.

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