Influence of gene polymorphism on the pharamacokinetics of c | 16853
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Influence of gene polymorphism on the pharamacokinetics of calcineurin inhibitors: In renal transplant patients from India


Kiran Kumar Vattam, Kamal Kiran Mukkavilli, Sireesha Moova, Pavani Upendram, Tarun Kumar Saha, Pragna Rao and Qurratulain Hasan

The calcineurin inhibitors(CIs), cyclosporine(CsA) and tacrolimus(Tac), are immunosuppressive drugs used to prevent rejection in patients with organ transplant. Both drugs have a narrow therapeutic range and show highly variable pharmacokinetics. This study will determine the role of gene polymorphisms involved in drug absorption and metabolism, ie ABCB1C3435T and CYP3A5A6986G, with respect to inter-individual variability in CsA/Tac levels, in a cohort of renal transplant recipients. Genotypes were assessed by PCR-RFLP in 201 renal transplant cases on immunosuppressive therapy for more than three months. ABCB1TT exhibited high CsA and Tac levels(1033.97±284.37ng/dl;8.57±3.86ng/dl) and blood C2levels/dose ratio(5.40±1.76;2.92±1.70) when compared to CC and CT genotypes. Similarly the CYP3A5GG genotype was associated with poor metabolism and showed increased CsA/Tac C2levels(1171±319.02ng/dl;9.85±3.71ng/dl) as well as levels/dose ratio(5.78±1.68;3.36±1.51). This suggests that CsA/Tac blood levels are regulated by these two genes. When gene-gene interaction was evaluated it was observed that ABCB1TT and CYP3A5GG genotypes showed the highest blood levels of Tac, however, in case of CsACYP3A5GG genotype is responsible for higher blood levels, irrespective of the ABCB1 genotype. These individuals would require a lower CsA/Tac dose to maintain therapeutic levels. Determination of these genotypes before renal transplant may alert clinicians and enable them to manage immunosuppression effectively and prevent complications.

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