Intestinal MDR1/ABCB1 level at surgery as a risk factor of acute cellular rejection in living-donor liver transplant patients.
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).


CONCLUSIONS
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.
Masuda
Satohiro
S
Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Kyoto Japan.
Goto
Maki
M
Fukatsu
Sachio
S
Uesugi
Miwa
M
Ogura
Yasuhiro
Y
Oike
Fumitaka
F
Kiuchi
Tetsuya
T
Takada
Yasutsugu
Y
Tanaka
Koichi
K
Inui
Ken-Ichi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007223:Infant; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012307:Risk Factors; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015415:Biomarkers; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus