Asian Journal of Pharmaceutical Research and Health Care

Azza A. M. H. Swar Aldahab , Abdallah. O. Elkhawad

Abstract

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G>A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G>A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G>A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G>A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

Keywords

CYP2C9*2, INR Stability, VKORC11639G>A, Warfarin

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Azza A. M. H. Swar Aldahab , Abdalla O. Elkhawad , Ahmed S. A. Elsayed , Hanan B. Eltahir

Abstract

Warfarin is a potent anticoagulant with a confirmed effectiveness when anticoagulation targets are attained, an issue, that is troublesome to reach due to the fact that warfarin has a narrow therapeutic index (NTI), that means they have a narrow window between their effective doses and those at which they produce adverse toxic effects. However, oral anticoagulation throughout genetics recommended a genotype guided dosing, but is it favourable over clinical based dosing? Objectives: To analyze the mean stable warfarin doses attained clinically within CYP2C9*2 and VKORC11639G>A wild-type and variant genotype status in Sudanese patients. Method: Genotyping for the CYP2C9*2 and VKORC1-1639G>A polymorphisms were accomplished with polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique. The mean stable warfarin dose per genotype was defined as the mean stable warfarin dose related to the stable INR within target range within a genotype of each of CYP2C9*2 or VKORC11639G> Agenes, using Analysis of Variance (ANOVA) as the statistical method. Results: Fifty-three stable patients with wild-type CYP2C9*1*1 genotype had a mean stable warfarin dose of 4.9 ± 2.1 mg, 5 patients who were heterozygous CYP2C9*1*2 genotype, had a mean stable warfarin dose of 5.0 ± 0.71mg, and 2 patients were homozygous mutant CYP2CP*2*2 genotype had a mean stable warfarin dose of 4.8 ± 0.3 mg. The results were statistically insignificant, P = 0.992.Sixteen unstable patients were of wild-type CYP2C9*1*1 genotype, 40 patients with heterozygous CYP2C9*1*2 genotype, and 4 with homozygous mutant CYP2CP*2*2 genotype, had mean stable doses of 5.32 ± 2.9, 6.5 ± 2.7 and 4.5 ± 0.71 mg respectively. The result was statistically insignificant, P = 0.508. Fifty-two stable patients were having wild-type VKORC1G/G genotype, 3 patients had heterozygous VKORC1G/A genotype and 3 patients had homozygous mutant VKORC1/AA genotype, these patients had mean stable doses of 5.41 ± 1.63, 4.8 ± 2.19 and 5.4 ± 0.99 mg respectively. The mean warfarin stable dose among homozygous mutant VKORC1A/A genotype was lower than among wild-type and heterozygous genotype profiles. This result was statistically not significant, P = 0.729.In the unstable group, 8 patients of wild-type VKORC1G/G genotype, had a mean stable warfarin dose of 7.34 ± 3.9 mg, 40 patients of heterozygous VKORC1G/A genotype had a mean stable warfarin dose of 5.21 ± 2.76 mg, and 10 patients of homozygous VKORC1A/A genotype had a mean stable warfarin dose of 4.3 ± 1.83 mg. The result was statistically insignificant, P = 0.067.Conclusion: In our study, as there were no significant differences between warfarin mean stable doses related to different CYP2C9*2 and VKORC11639G>A genotypes, the evidence is not satisfactory to conclude that the conventional use of genotype guided warfarin dosing will correct stable warfarin dose among Sudanese patients.

Keywords

Genotype, Stable Dose, Warfarin

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