BACKGROUND: Although the prevention of immunologic reactions with sufficient immunosuppression prolongs graft and patient survival rates, the large interindividual variation in tacrolimus pharmacokinetics interferes with treatment. In this study we have examined whether intestinal MDR1 (ABCB1) is a potential biomarker predicting the occurrence of acute cellular rejection, as well as a factor to predict absorption of tacrolimus, after living-donor liver transplantation. METHODS: By use of tissue specimens of intestinal mucosa (n = 164) obtained at surgery, the messenger ribonucleic acid (mRNA) expression of intestinal MDR1 and cytochrome P450 (CYP) 3A4 was quantified. RESULTS: The probability of acute cellular rejection during the first 10 days after surgery was significantly associated with the average trough concentration of tacrolimus between postoperative days 2 and 4 (45.1% for <7 ng/mL versus 22.9% for >7 ng/mL,P= .0040). High levels of MDR1 were associated with an episode of acute cellular rejection before postoperative day 10 (odds ratio, 2.306 [95% confidence interval, 1.058-5.028]) and with a poor survival rate during the first postoperative year (odds ratio, 7.413 [95% confidence interval, 1.567-36.073]). The mRNA expression level of MDR1 was inversely correlated with the tacrolimus concentration-oral dose ratio during the initial 4 days after surgery in patients with a graft-to-recipient weight ratio greater than 1.5 (r= -0.6798, P< .0001) and those with a graft-to-recipient weight ratio of less than 1.5 (r= -0.7180, P< .0001). CONCLUSION: The enterocyte MDR1 mRNA level was suggested to be a risk factor for acute cellular rejection and death after surgery. Therefore obtaining a sufficient tacrolimus blood level via this molecular information-based initial dosage adjustment may enable the episode of acute cellular rejection after liver transplantation to be reduced.
BACKGROUND: Although the prevention of immunologic reactions with sufficient immunosuppression prolongs graft and patient survival rates, the large interindividual variation in tacrolimus pharmacokinetics interferes with treatment. In this study we have examined whether intestinal MDR1 (ABCB1) is a potential biomarker predicting the occurrence of acute cellular rejection, as well as a factor to predict absorption of tacrolimus, after living-donor liver transplantation. METHODS: By use of tissue specimens of intestinal mucosa (n = 164) obtained at surgery, the messenger ribonucleic acid (mRNA) expression of intestinal MDR1 and cytochrome P450 (CYP) 3A4 was quantified. RESULTS: The probability of acute cellular rejection during the first 10 days after surgery was significantly associated with the average trough concentration of tacrolimus between postoperative days 2 and 4 (45.1% for <7 ng/mL versus 22.9% for >7 ng/mL,P= .0040). High levels of MDR1 were associated with an episode of acute cellular rejection before postoperative day 10 (odds ratio, 2.306 [95% confidence interval, 1.058-5.028]) and with a poor survival rate during the first postoperative year (odds ratio, 7.413 [95% confidence interval, 1.567-36.073]). The mRNA expression level of MDR1 was inversely correlated with the tacrolimus concentration-oral dose ratio during the initial 4 days after surgery in patients with a graft-to-recipient weight ratio greater than 1.5 (r= -0.6798, P< .0001) and those with a graft-to-recipient weight ratio of less than 1.5 (r= -0.7180, P< .0001). CONCLUSION: The enterocyte MDR1 mRNA level was suggested to be a risk factor for acute cellular rejection and death after surgery. Therefore obtaining a sufficient tacrolimus blood level via this molecular information-based initial dosage adjustment may enable the episode of acute cellular rejection after liver transplantation to be reduced.
Authors: Julia M Barbarino; Christine E Staatz; Raman Venkataramanan; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2013-10 Impact factor: 2.089
Authors: Ahmed F Hawwa; Patrick J McKiernan; Michael Shields; Jeff S Millership; Paul S Collier; James C McElnay Journal: Br J Clin Pharmacol Date: 2009-09 Impact factor: 4.335
Authors: Eliecer Coto; Beatriz Tavira; Beatriz Suárez-Álvarez; Carlos López-Larrea; Carmen Díaz-Corte; Francisco Ortega; Victoria Alvarez Journal: Kidney Int Suppl (2011) Date: 2011-08