Metoprolol metabolism via cytochrome P4502D6 in ethnic populations.
OBJECTIVE
The objective of this study was to determine whether metabolism via cytochrome P4502D6 (CYP2D6) was higher in Black subjects than White subjects.


METHODS
Ten Black and 10 White healthy male volunteers who were phenotyped CYP2D6 extensive metabolizer phenotypes participated in this randomized, cross-over study in which metoprolol was used as a model CYP2D6 substrate. In both study phases, subjects received oral rac-metoprolol tartrate (200 mg); during one phase, subjects also took quinidine sulfate (100 mg) daily beginning 3 days before the dose of metoprolol. Plasma samples were collected for 12 and 24 hr after the dose in the metoprolol and metoprolol plus quinidine phases, respectively. Metoprolol enantiomer concentrations were determined by chiral HPLC with fluorescence detection.


RESULTS
S-metoprolol areas under the concentration vs. time curves during the metoprolol phase were 879 +/- 600 ng/ml*hr in White subjects vs. 984 +/- 653 ng/ml*hr in Black subjects. During inhibition of CYP2D6-mediated metabolism with quinidine, S-metoprolol areas under the concentration vs. time curves were 2515 +/- 749 and 2719 +/- 742 in White and Black subjects, respectively. Metoprolol elimination half-lives in both groups were approximately doubled by quinidine. Mean S-metoprolol/R-metoprolol ratios were 1.39 in both racial groups during the metoprolol phase, and during the metoprolol plus quinidine phase were 0.89 and 1.03 in White subjects and Black subjects, respectively (p < 0.05, Blacks vs. Whites). The percentage of metoprolol metabolism inhibited by quinidine was similar between Blacks and Whites (e.g., 66 +/- 15% and 64 +/- 25% of S-metoprolol apparent oral clearance in Blacks and Whites, respectively).


CONCLUSIONS
We conclude that there are no differences between Black subjects and White subjects in metabolism via CYP2D6. There were also no racial differences in the contribution of CYP2D6 to overall metoprolol metabolism. The results of this study suggest that drugs are primarily metabolized by CYP2D6 will not exhibit racial differences in their disposition.
Johnson
J A
JA
Department of Clinical Pharmacy, University of Tennessee-Memphis 38163, USA.
Burlew
B S
BS
D000328:Adult; D000959:Antihypertensive Agents / Q000378:metabolism*; D044383:Black People; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000378:metabolism*; D008968:Molecular Conformation; D011802:Quinidine / Q000494:pharmacology; D044465:White People
D000959:Antihypertensive Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D011802:Quinidine