Establishment Of Multi-site Prediction Model Of Tacrolimus Metabolism And New-onset Hypertension After Liver Transplantation

Aim:（1）The purpose of the current study was to investigate individualized therapy of tacrolimus（Tac）,as well as complications after liver transplantation（LT）with the known genetic determinants and clinical factors.（2）The effect of solute carrier family 28 member 3（SLC28A3）on tacrolimus disposition and new-onset hypertension（NOHP）after liver transplantation（LT）remains unclear.Methods:（1）In this retrospective study,two cohorts（N=170）from the China Liver Transplant Registry（CLTR）database were included.Trainging set and validation set use drug-metabolizing enzymes and transporter（DMET）chip and real-time quantitative PCR respectively.（2）SLC28A3 sites related to Tac metabolism were screened by DMET chip in the liver transplantation patients in the test group（N=79）.As to the validation group（N=90）,real-time quantitative PCR was used to verify the above loci.Results:（1）Both donors’CYP3A5^*3 and recipients’CYP3A4^*1G had a correlation with Tac pharmacokinetics at four weeks（all P<0.05）,except recipients’CYP3A4^*1G nearly had an association at week 2（P=0.055）.The model of donors’CYP3A5^*3,recipients’CYP3A4^*1G,and total bilirubin（TBL）,for the prediction of Tac disposition,was better than donors’CYP3A5^*3 only at week 1,2,and 3（P=0.01,P=0.007,and P=0.01,respectively）,but not apparent at week 4（P=0.297）.Besides,when the P value was greater than or equal to 0.6685 after considering the false-positive rate R=10%,the patients were considered to have a faster metabolism,according to the mentioned model.Interestingly,we found that if more than or equal to two alleles A were present in the combination of donors’CYP3A5^*3 and recipients’CYP3A4^*1G genotype,there was a lower Tac C₀/D ration at week 1,2,and 3（P<0.001,P=0.001,and P<0.001 respectively）,except at week 4（P=0.082）,and the probability of new-onset hypertension was lesser（P<0.001）.（2）Rs7853758 in recipients’SLC28A3 could predict tacrolimus pharmacokinetics in two sets.The model of donors’CYP3A5 rs776746and recipients’CYP3A4 rs2242480 could predict tacrolimus metabolism at week 1 and the model of donors’CYP3A5 rs776746,recipients’CYP3A4rs2242480,recipients’SLC28A3 rs7853758 and hemoglobin could predict tacrolimus disposition at weeks 2,3 and 4 respectively.Besides,recipients’SLC28A3 rs7853758 was a new risk factor of new-onset hypertension（NOHP）after LT.Conclusions:These data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention,early diagnosis of NOHP in Chinese LT recipients.