Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients.
The role of intestinal P-glycoprotein (encoded by the MDR1/ABCB1 gene) and/or metabolic enzyme CYP3A4 for tacrolimus therapy was examined in recipients of living-donor liver transplantation (LDLT), under the hypothesis that these proteins are factors for pharmacokinetic variability. The intestinal mRNA expression level of MDR1 and CYP3A4 was evaluated by real-time polymerase chain reaction (PCR), using the upper jejunum from a part of the Roux-en-Y limb for biliary reconstruction at LDLT. For 7 days postoperatively, good inverse correlation was found between the tacrolimus concentration/dose (C/D) ratio and the intestinal mRNA level of MDR1 (r = -0.776), but not of CYP3A4 (r = -0.096), in the 46 cases. After classifying the patients according to median of the intestinal MDR1 mRNA expression, the oral dose of tacrolimus in the high-MDR1 group was approximately twofold higher than in the low-MDR1 group (P < .001), whereas its trough level was similar between the two groups. In addition, the correlation between the intestinal MDR1 mRNA level and the tacrolimus C/D ratio was confirmed with a larger population (r = -0.645, n = 104). Using the regression line between the intestinal MDR1 mRNA level and tacrolimus C/D ratio, we could prospectively predict the individual C/D ratio of tacrolimus immediately after LDLT. Known genetic variations of the MDR1 gene had no effect on intestinal MDR1 mRNA level and tacrolimus C/D ratio in LDLT patients. This suggests that the intestinal mRNA level of MDR1 is a useful molecular marker for determination of the personalized oral dose of tacrolimus in recipients of LDLT immediately after surgery.
Masuda
S
S
Department of Pharmacy, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
Goto
M
M
Okuda
M
M
Ogura
Y
Y
Oike
F
F
Kiuchi
T
T
Tanaka
K
K
Inui
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007413:Intestinal Mucosa; D016031:Liver Transplantation / Q000276:immunology* / Q000379:methods; D019520:Living Donors; D012333:RNA, Messenger / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005819:Genetic Markers; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus