Role Of CYP2C9 Polymorphism In Losartan Pharmacokinetics And Pharmacodynamics

Cytochrome oxidase P450 2C9 (CYP2C9) is an important drug-metabolizing emzyme in human liver, share about 20% of total CYPs in human liver microsome. 10% clinical medicines are metabolized by CYP2C, including tolbutamide, s-warfarin, phenytoin, glipizide, glibenclamide, losartan, irbesartan and many non-steroid anti-inflammatory drugs, such as ibuprofen, lormoxicam, diclofenac, naproxen and so on. The change of CYP2C9 activity is a significant factor of racial differences and individual differences in clinical medication and drug interactions. The study of CYP2C9 is a hot spot in pharmacogenetics.CYP2C9 has genetic polymorphism, there are 30 alleles have been found. The first identified alleles are CYP2C9^*2-^*6, among them, CYP2C9^*2 and CYP2C9^*3 are most common and are frequently researched one. Recently, as large samples of CYP2C9 gene sequencing, CYP2C9^*7-^*30 have been found. In newfound mutants, only CYP2C9^*13, ^*16, ^*17 and ^*19 have been detected in Chinese population, and the frequencies are low, just between 0.9%-2%. They are T269C (Leu-90-Pro), A895G (Thr-299-Ala), C 1144T (Pro-382-Ser), and G1362C (Gln-454-His). The genetic polymorphism of CYP2C9 can lead to the change of its activity. The functional mutants lead the decrease of CYP2C9 activity, so the therapeutic effects of its substrate drugs can be reduced or more adverse reactions should occur.Losartan is an angiotensinamideâ…¡receptor antagonistic drug and used for hypertension. Losartan mainly metabolized to E-3174 by CYP2C9. CYP2C9^*2 and ^*3 can decrease the catalytic activity of CYP2C9, and reduce the quantity of E-3174. There are many drugs can induce CYP2C9. To combine them with losartan may occur interactions in pharmacokinetics and pharmacodynamics. But the genetic polymorphisms of CYP2C9 can affect in these interactions or not have not been reported. To study how the genetic polymorphisms of CYP2C9 influence the metabolism of losartan can explain why there are individual differences in losartan treatment and can guide clinical retional administration.So this study focus on finding out whether CYP2C9^*13, ^*16, ^*17 and ^*19 mutants influence the metabolism of losartan in vitro model. To investigate CYP2C9^*3 and ^*13 mutants whether effect on the pharmacodynamics and pharmacokinetics or not, and in the sametime, to detect these polymorphisms influence on the interactions of losartan which is led by introduction and inhibition of CYP2C9 in clinical research. This subject can offer molecular level explain for individual difference of losartan, and guide personalized medicine.The present series studies found that:1. In recombine COS-7 cell model, CYP2C9^*13 and ^*16 can decrease the catalytic activity of CYP2C9 to losartan, CYP2C9^*17 and^*19 have no effect on catalytic activity of losartan. Chinese people who carry CYP2C9^*13 or ^*16 mutant allele may be losartan poor metabolizer.2. In Chinese healthy volunteers, CYP2C9^*3 and CYP2C9^*13 alleles can reduce losartan metabolize to E-3174, and degrade the depressurization of losartan.3. CYP2C9^*1/^*3 and ^*1/^*13 mutant alleles could reduced the decreased extents of AUC and T_1/2 of larsartan, increased the dereased extents of AUC and C_max, of E-3174, and prolonged T_1/2 of E-3174 aider the induction of rifampicin. In the other hand, rifampicin could enhance depressurization of losartan, CYP2C9^*1/^*3 and ^*1/^*13 mutant alleles could strengthen this kind of pharmacodynamics interaction.4. Vorionazole can interact with losartan in pharmacokinetics and pharmacodynamics, and lower the quantity of E-3174, reduce the depressurization of losartan. CYP2C9^*3 and ^*13 mutant alleles can strengthen this drug interaction, and its clinical significance should be further studied.In a word, this research provides explaination to individual differences in pharmacokinetics and pharmacodynamics of losartan and its interaction, from whole, cell level and molecular level.