Debrisoquine and S-mephenytoin hydroxylation polymorphism was studied inrn115 healthy unrelated Ethiopian volunteers after coadministration of debrisoquinern(lOmg) with S-mephenytoin (lOOmg). The ratio of the S to the R enantiomers ofrnmephenytoin and of debrisoquine to 4-0H debrisoquine in 0-8 hr urine samples wererndetermined using GC. Debrisoquine and S-mephenytoin are metabolized by CYP2D6rnand CYP2CI9 respectively. CYP2D6 and CYP2C19 show genetic polymorphism,rndividing the population into Extensive metabolizers (EMs) and Poor metabolizersrn(PMs). The frequency of the PM phenotype is a subject of a pronounced inter-ethnicrndifference.rnTwo subjects (1.7%) are classified as a PMs (MR > 12.6) with respect tornCYP2D6. The debrisoquine MRs are trimodally distributed with a greater part ofrnthe population located in the MR interval of 1 - 10. The low prevalence of PMs isrndue to a lower frequency of a defective CYP2D6 allele. Using a combination ofrnRFLP, SSCP and PCR, subjects were genotyped for the known mutations in thernCYP2D6 locus. Using XbaI and EcoRl RFLP, 11.5kb, 44kb and 42kb haplotypesrnassociated with gene deletion, defective CYP2D locus and gene duplication respectivelyrnwere detected. Defective CYP2D6A, CYP2D6B and exon 1 mutations were detectedrnusing PCR. SSCP and PCR were used to genotype the CYP2D6C mutations.rnNo individual had either the CYP2D6A or the CfP2D6C allele. The allelernfrequencies for CYP2D6B, CYP2D6D and exon 1 mutation was 1.3%, 3% and 9.8%rnrespectively. The allele frequency of the duplicated CYP2D6 gene (42 kb allele) isrnsignificantly higher (12.9%) among Ethiopians than in any other population studied.rnFurthermore, the RFLP analysis indicated the existence of alleles carrying 3, 4 andrneven 5 active CYP2D6 genes in tandem.rnFor S-mephenytoin hydroxylase (CYP2CI9), six subjects (5.3%) with SIRrnratio greater than 0.9 phenotyped as PMs. Three of them were homozygousrn(CYP2Cl9mlICYP2Cl9ml) and the rest heterozygous (CYP2Cl9mllCYP2Cl9m2) forrnmutated allele of CYP2C19. CYP2Cl9ml and CYP2Cl9m2 account for 75% and 25%rnof defective alleles respectively in PMs. These results indicate that CYP2C19rngenotyping analysis for both CYP2Cl9ml and CYP2Cl9m2, enables one to apparentlyrnpredict about 100% of the phenotypes.