The human CYP2C subfamily further information contains four highly homologous genes �� 2C8, 2C9, 2C18 and 2C19 �� which are located in a cluster Inhibitors,Modulators,Libraries on chromo some 10. 3 CYP2C9 is the main CYP2C enzyme, constituting 20 per cent of total human liver micro somal P450 content. 4 CYP2C9 and CYP2C19 genes each contain nine exons and encode Inhibitors,Modulators,Libraries proteins of 490 amino acids in length. Although these genes are highly homologous, the enzymes differ in terms of substrate speci?cities. 5 Major variations in the occurrence of polymorphisms in both CYP2C9 and CYP2C19 genes have been reported in various populations. CYP2C9 variants CYP2C9 2 and CYP2C9 3 are the most common and occur at frequencies of 0. 11 and 0. 08, respectively, in Caucasians. 6 Population based pharmacokinetics pharmacody namics modelling of their effects has been explored for revising labels of CYP2C9 substrate drugs.
7 Testing Inhibitors,Modulators,Libraries for CYP2C9 genotypes can be used to predict the starting dose of Inhibitors,Modulators,Libraries the anticoagulant drug warfarin to avoid excessive bleeding episodes. 8 Other drugs affected by CYP2C9 polymorphism are the antidiabetic agents glipizide and tolbutamide, the anti epileptic agent phenytoin, the antihypertensive drug losartan and non steroidal anti in?ammatory drugs such as ibuprofen and diclofenac. 9 CYP2C19 metabolises omeprazole, diazepam and proguanil to a major extent. The common allelic var iants, such as CYP2C19 2 and CYP2C19 3, cause reduced enzyme activity and contribute to the poor metabolism of substrate drugs. 10 A polymorphism in the promoter region has, however, been associated with increased enzyme activity.
11 Individuals carrying this variant may therefore require a higher dosage in order to achieve the therapeutic effect. CYP2D6 metabolises a wide range of drugs, such as antiarrhythmic agents, tricyclic antidepressants, neuroleptics and anti cancer agents. 12 CYP2D6 is the most polymorphic CYP with alleles causing a spec trum of phenotypic responses. Inhibitors,Modulators,Libraries The presence of mul tiple copies of the gene results in individuals described as ultra rapid metabolisers. For example, individuals carrying duplicated or multi duplicated active CYP2D6 genes are very common among Ethiopians, compared with Caucasian, Oriental and other Black populations. 13 By contrast, whole gene deletions causing poor metaboliser phenotypes, have been observed across all populations. The African speci?c alleles CYP2D6 17 and CYP2D6 29 cause reduced enzyme activity.
individuals homozygous for these alleles are classi?ed as intermediate metabolisers. Overall, PS-341 Africans metabolise CYP2D6 substrates at a slower rate than Caucasians owing to the higher prevalence of these reduced function alleles. 14 So far, NAT2 has been found to comprise 19 major known haplotypes. Important drugs metab olised by this enzyme include the anti tuberculosis drug isoniazid and the antibiotic co trimoxazole.