Türk böbrek nakilli hastalarda üridine difosfat-glukuronoziltransferaz polimorfizmlerinin mikofenolik asit’in kan konsantrasyonları üzerine etkileri

Abstract

Amaç: Mikofenolik asit’in (MPA) farmakokinetiğinde bireyler arasında farklılıklar vardır. MPA öncelikle uridin difosfat-glukuronosiltransferazlar (UGT) tarafından metabolize olur. UGT2B7, MPA glukuronidasyonu için önemli bir UGT’dir. Çalışmanın amacı, Türk böbrek nakilli hastalarda UGT2B7 His268Tyr (802C>T) polimorfizmlerinde MPA farmakokinetiğini incelemektir.

Gereç ve Yöntem: Çalışmaya renal transplant yapılmış, 65 hasta dahil edildi. UGT2B7 His268Tyr (802C>T) genotiplemesi PCR-RFLP kullanılarak yapıldı. MPA konsantrasyonları Klonlanmış Enzim Donör Immunoassay (CEDIA) ile belirlendi. Tüm hastalar çalışma süresi boyunca akut rejeksiyon ve greft fonksiyonu açısından izlendi.

Bulgular: Hastalar arasında UGT2B7 (802C>T) CC, CT ve TT genotip frekansları sırasıyla 24 (%36,9), 36 (%55,4) ve 5 (%7,7) idi. Üçüncü ve altıncı aylarda MPA düzeyleri UGT2B7 (802C>T) TT taşıyıcılarında CT ve CC taşıyanlara göre sırasıyla istatistiksel olarak anlamlı derecede yüksek bulundu (p=0,038, p=0,021). MPA’nın doz/kan konsantrasyonu oranı nakil sonrası altıncı ayda TT genotipi taşıyanlarda CC ve CT genotipi taşıyanlara göre daha yüksekti (p=0,042). TT genotipi taşıyan bireyler sırasıyla CC ve CT genotiplerine kıyasla üçüncü ve altıncı ayda düşük doz gereksinimleri göstermişlerdir (p=0,109, p=0,238). Ayrıca UGT2B7 (802C>T) polimorfizmi ile akut rejeksiyon arasında bir ilişki bulunmamıştır (p>0,05).

Sonuç: Bizim sonuçlarımız, böbrek nakilli hastalarda UGT2B7 (802C>T) polimorfizmi ile MPA farmakokinetiği arasında bir korelasyon olduğunu göstermiştir. UGT2B7 polimorfizminin saptanması, en uygun MPA kan konsantrasyonları hedefi belirlenmesine yardımcı olabilir.

Keywords

• Böbrek nakli; farmakogenetik; immünsupresif tedavi; polimorfizm; mikofenolik asit

Effect of uridine diphosphate-glucuronosyltransferase polymorphisms on the plasma concentrations of mycophenolic acid in Turkish renal transplant patients

Abstract

Objective: The pharmacokinetics of mycophenolic acid (MPA) differ among individuals. MPA is primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT), and UGT2B7 is an important UGT for the glucuronidation of MPA. This study aimed to examine the pharmacokinetics of MPA in Turkish renal transplant patients with UGT2B7 His268Tyr (802C>T) polymorphisms.

Materials and Methods: Sixty-five renal transplants patients were included in this study. UGT2B7 (802C>T) genotyping was performed using PCR-RFLP. Concentrations of MPA were determined using a cloned enzyme donor immunoassay (CEDIA). All patients were monitored for acute rejection and graft function during the study period.

Results: The UGT2B7 (802C>T) CC, CT, and TT genotype frequencies among patients were 24 (36.9%), 36 (55.4%), and 5 (7.7%) respectively. At three and six months post-transplant respectively, levels of MPA were significantly higher in UGT2B7 (802C>T) TT carriers than in CT and CC carriers (p=0.038; p=0.021). The ratio of plasma concentration to MPA dosage for patients with 802C>T TT genotype was higher than that of CC and CT genotypes at six months post-transplant (p=0.042). Individuals carrying the TT genotype demonstrated lower dose requirements at three and six months compared with those of the CC and CT genotypes respectively (p=0.109, p=0.238). Additionally, there was no association found between UGT2B7 (802C>T) polymorphism and acute rejection (p>0.05).

Conclusion: Our results demonstrated a correlation between the UGT2B7 (802C>T) polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT2B7 polymorphism may be helpful for determining the optimum dose of MPA to achieve the target plasma concentration. 

Keywords

• Renal transplantation; pharmacogenetics; immunosuppressive therapy; polymorphism; mycophenolic acid

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