COMPARISON OF 3 CYP2D6 PROBE SUBSTRATES AND GENOTYPE IN GHANAIANS, CHINESE AND CAUCASIANS

The ability to metabolize CYP2D6 substrates sparteine, debrisoquine, a nd dextromethorphan was studied in healthy Caucasian (n = 20), Ghanaia n (n = 21), and Chinese (n = 22) CYP2D6 extensive metabolizers. Genoty pe analysis for the CYP2D61, *3, *4, *5, *9, *10, and *17 alleles was performed. Interethnic differences in the disposition of the probe dr ugs were found among the extensive metabolizers; extensive metabolizer status was confirmed by phenotype and genotype analysis. The mean met abolic rate was lower for Caucasians than for Ghanaians for sparteine (P < 0.02) and for both Ghanaians and Chinese for debrisoquine (P < 0. 02). Correlation comparisons resulted in lower pairwise correlation co efficients in Ghanaians compared with Chinese and Caucasians for every combination of probe substrates. In addition, in Chinese and Caucasia ns, metabolic rates for each pair of probe drugs were significantly co rrelated (P < 0.002), but in Ghanaians the dextromethorphan metabolic rates were not correlated to either sparteine or debrisoquine (P < 0.0 5), Even when only those with a CYP2D61/*1 genotype were included in the correlation calculations, the Ghanaians had very low correlation c oefficients (r(s) - 0.02-0.2, n = 9); much lower than those found in C aucasian (r(s) 0.78-0.92, n = 14) or Chinese (r(s) 0.54-0.96, n = 7) i ndividuals. Quinidine had significantly less affect on sparteine metab olic rates in Ghanaians than both Caucasians and Chinese (P < 0.02). I n addition, five of the 21 Ghanaian individuals had dextromethorphan m etabolic ratios which were unaffected by quinidine. These individuals also had differences in urinary recovery of dextromethorlphan and its metabolites when compared to the other Ghanaian individuals. These res ults confirm the large ethnic differences in probe drug metabolism and quinidine sensitivity among these ethnic groups. They also suggest th at the Ghanaians have an additional unidentified allele(s) with altere d substrate specificity and quinidine sensitivity which is currently g enotyped as CYP2D61. Pharmacogenetics 8:325-333 (C) 1938 Lippincott-R aven Publishers.