Abstract
This study in human liver microsomes was undertaken to establish whether paroxetine stereoselectively inhibits the oxidative metabolism of metoprolol in vitro, and whether the in vivo observed magnitude of the paroxetine-metoprolol interaction was predictable from these in vitro data. Two distinct approaches were used: inhibitory effect of paroxetine on 1) the formation of α-hydroxymetoprolol andO-desmethylmetoprolol from the individual metoprolol enantiomers and 2) on the depletion of the enantiomers from the incubation mixture. Nonspecific binding of both metoprolol and paroxetine to human liver microsomes was also investigated. Whereas metoprolol displayed negligible binding, paroxetine was extensively bound to microsomal proteins. This was taken into account in order to obtain unbiased Ki values and unbound concentrations of paroxetine. In the substrate depletion experiments, the intrinsic clearance (CLint) of (R)-metoprolol was larger than that of (S)-metoprolol. Paroxetine caused a concentration-dependent decrease in CLint of both enantiomers and abolished the stereoselectivity. In the metabolite formation experiments paroxetine did not stereoselectively affect α-hydroxylation, but preferentially inhibited theO-demethylation of the (R)-enantiomer versus the (S)-enantiomer. The use of unbound paroxetine concentrations in the two in vitro methods yielded comparable predicted increases in area under the curve (1.7–1.9 and 2.2–2.5 for (S)- and (R)-metoprolol, respectively) but underestimated the in vivo observed changes of about 7- and 10-fold, respectively. In conclusion, this study showed that paroxetine abolishes the stereoselective metabolism of metoprolol due to a stereoselective inhibition of the O-demethylation toward (R)-metoprolol. Furthermore, the extent of the in vivo metoprolol-paroxetine interaction was substantially underestimated by either one of the two in vitro approaches used when a competitive mechanism was assumed.
Footnotes
-
Send reprint requests to: F. M. Belpaire, Heymans Institute of Pharmacology, Ghent University Medical School, 9000 Ghent, Belgium. E-mail: Frans.Belpaire{at}rug.ac.be
-
This study was supported by Grant G.0011.97 from the National Fund for Scientific Research, Belgium and by Grant 0104197 from the Ghent University Research Foundation.
- Abbreviations used are::
- EM
- extensive metabolizer
- α-OHM
- α-hydroxymetoprolol
- O-DMM
- O-desmethylmetoprolol
- HPLC
- high-performance liquid chromatography
- CV
- coefficient of variation
- AIC
- Akaike Information Criterion
- AUC
- area under the curve
- fu,mic
- unbound fraction of paroxetine in the microsomal compartment
- Ki,app
- apparent inhibition constant
- Received August 14, 2000.
- Accepted January 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|