| Abstract:bjective:①To summarize the individual difference of blood concentration and dosage of tacrolimus during the early period in patients underwent liver transplantation.②To provide guidance of CYP3A4/5and MDRI gene polymorphism to the individualized medication of tacrolimus during the early period after liver transplantation. we explore the relationship between gene polymorphism of CYP3A4/5, MDRI and the individual difference of blood concentration and dosage of tacrolimus, the recovery of hepatic and renal function during early period after liver transplantation. Methods:Through analyzing the38liver transplantation patients in our hospital, whose basic immunosuppressive agent is tacrolimus, we determine the gene polymorphism of CYP3A4/5and MDRI with gene chip microvibration method. Then we used the EMIT(enzyme multiplied immunoassay technique) to determine the whole blood trough concentration of tacrolimus and collected the dosage(D), concentration(C), the corrected ratio of C/D, serum creatinine, alanine aminotransferase(ALT), total bilirubin, blood coagulation function(INR) of the patients in the lth,2th,4th week after the liver transplantation. Results:①The corrected ratio of C/D and the oral requirement of tacrolimus during the early period after liver transplantation varied considerably in different individual.②Among the38liver transplantation patients, there are14CYP3A4C/C,19CYP3A4C/T,4CYP3A4T/T and1 indetectable as hypothetical missing data. The occurrence frequency of each genotype is37.8%,51.4%,10.8%. Among the three groups, CYP3A4C/C group has the lowest requirement of tacrolimus (P<0.05) and the highest corrected C/D ratio in the1th week of postoperation(P<0.05). The corrected C/D ratio of CYP3A4C/C group is significantly higher than CYP3A4C/T group(P<0.05). There were no statistical differences in the4th week. The recovery speed of ALT in CYP3A4C/C group was slower than the CYP3A4C/T in the lth week of postoperation (P<0.05) while the CYP3A4C/C group recovered slower than CYP3A4T/T in the4th week after surgery(P<0.05). The recovery speed of serum creatinine and INR in CYP3A4C/C group is slower than the CYP3A4C/T group in the2th after surgery(P<0.05).③Among the38liver transplantation patients, there are5CYP3A5A/A,15CYP3A5A/G,18CYP3A5G/G. The occurrence frequency of each genotype is13.1%,39.5%,47.4%. Among the three groups, CYP3A5G/G group has the lowest requirement of tacrolimus (P<0.05) and the highest corrected C/D ratio (P<0.05). The recovery speed of serum creatinine in CYP3A5G/G group is slower than the CYP3A5A/G group in the2th,4th week after surgery(P<0.05). The recovery speed of ALT in CYP3A5G/G group was slower than the CYP3A5A/A group in the2th week after operation(P<0.05) While the CYP3A5G/G group recovered slower than the other two groups in the4th week after surgery(P<0.05). The recovery speed of INR in CYP3A5G/G group was slower than the CYP3A5A/G group in the2th week after surgery(P<0.05).④The distribution of gene polymorphism of MDRI is different in various sites. There are no significant statistical differences in the dosage of tacrolimus and the corrected ratio of C/D among MDR1C1236T, G2677AT and C3435T group. The recovery speed of ALT in C3435T wild homozygous group was slower than the mutant homozygous group in the1th,2th week after surgery(P<0.05). While the G2677AT wild homozygous group recovered slower than the heterozygous and mutant homozygous group in the lth week after surgery(P<0.05).And the G2677AT wild homozygous group recovered slower than mutant homozygous group in the2th week of postoperation(P<0.05). Conclusions:①There are large individual differences in tacrolimus dose early requirement after liver transplantation in daily clinical practice.②The gene polymorphism of CYP3A4and CYP3A5may be the key point that causes the significant individual pharmacokinetics differences while MDR1has no such effect.③The gene polymorphism of CYP3A4and CYP3A5is helpful in the guidance of early individual medication of tacrolimus and has a better feasibility and application prospects.④The slow metabolism of CYP3A4(C/C) and CYP3A5(G/G) require a lower dose of tacrolimus to reach the target blood concentration than that of fast metabolism of CYP3A4(C/T, T/T) and CYP3A5(A/A,A/G) respectively.⑤The gene polymorphism of CYP3A4and CYP3A5may be one of the important factors affecting the early stage recovery of renal and hepatic function after the liver transplantation. The gene polymorphism of MDR1C3435T and G2677AT may also be one of the important factors affecting the early stage recovery of ALT after the liver transplantation. |
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