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Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired. [ABSTRACT FROM AUTHOR]

Background: CYP1A2 and CYP2A6 are polymorphic drugmetabolising enzymes that are also implicated in the activation of procarcinogens in humans. Some of their alleles and haplotypes, often varied in prevalence across populations, are thought to influence activity despite the known contribution of environmental factors. This study assessed the potential influence of some genetic variants of CYP1A2 and CYP2A6 on metabolic phenotypes in Nigerians. Methods: Genomic DNA was extracted from blood samples of 100 healthy, unrelated subjects for whom CYP1A2 and CYP2A6 phenotypes had previously been determined, alongside an additional 80 other individuals for whom phenotype data were unavailable. The samples were screened for CYP1A2 (*1C,*1D,*1E,*1F, *3,*4,*6,*7) and CYP2A6 (*9,*11,*17) alleles using the Sequenom MassARRAY platform for some alleles and direct Sanger sequencing for others. The genetic data acquired were subsequently analysed for haplotypes and assessed for concordance with phenotypes. Results: All five CYP1A2 haplotypes (CYP1A2*1F, 1J, 1N, 1L, 1W) identified in the Nigerian population were not significantly predictive of metabolic phenotypes. Heterozygous CYP1A2*1J carriers and homozygous CYP1A2*1W carriers showed statistically insignificant decrease in CYP1A2 activity. The CYP2A6*9/*17 genotype was, however, significantly associated with the CYP2A6-poor metabolic phenotype, whereas CYP2A6*9 or CYP2A6*17 alone did not show any such association. CYP2A6*11 was not detected in the population. Conclusions: Our findings suggest that CYP1A2 alleles or haplotypes were not predictive of metabolic phenotypes in the Nigerian population. Carriers of CYP2A6*9/*17 genotype are likely to be poor metabolisers of CYP2A6 substrates and may experience adverse reactions or poor efficacy while using drugs metabolised mainly by CYP2A6. [ABSTRACT FROM AUTHOR]

Background: CYP1A2 and CYP2A6 are polymorphic enzymes that metabolise several compounds of clinical importance. This study investigated the prevalent phenotypes of these enzymes and the influence of age and sex on enzyme activity in a Nigerian population. Methods: Caffeine (110 mg) was administered to each of 129 healthy, unrelated subjects (85 males and 44 females) who were non-smokers. Urine voided within 7 h after caffeine administration was collected for a high performance liquid chromatographic assay of caffeine (137X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2 activity was measured as a ratio of (17U+17X) to 137X, while 17U/17X served as marker for CYP2A6. Transformed data were analysed and the influences of age and sex on activity were also determined. Results: Distribution of CYP1A2 activity in the population was bimodal with a mean±SD of 0.82±0.41, while that of CYP2A6 was trimodal with a mean±SD activity of 0.27±0.42 of the log-transformed urinary molar ratio of metabolites. The influences of age and sex on enzyme activity for both CYP1A2 and CYP2A6 were not significant (p>0.05). Conclusions: The study established the prevalence of polymorphism in phenotypes of CYP1A2 and CYP2A6 activity in the Nigerian population, but no influence of age and sex on enzyme activity was observed in this population. [ABSTRACT FROM AUTHOR]