title: Relation between mRNA expression level of multidrug resistance 1/ABCB1 in blood cells and required level of tacrolimus in pediatric living-donor liver transplantation.
abstract: It has been difficult to set an individualized therapeutic window of tacrolimus after organ transplantation, because of wide interindividual variation of responsiveness to immunosuppressive therapy. In this study, we examined the significance of multidrug resistance 1 (MDR1) in the peripheral blood cells by comparing the trough concentration of tacrolimus with the occurrence of acute cellular rejection (ACR) in retrospectively collected pediatric living-donor liver transplant patients, who were enrolled after obtaining written informed consent. No significant difference in the intraindividual variation in MDR1 mRNA expression in the peripheral blood cells was observed between postoperative days 3 and 7. The average trough concentration of tacrolimus during the 15-day postoperative period was significantly higher in the event-free patients than in those who experienced ACR (21 of 44 cases), and they had higher levels of blood MDR1 mRNA. In addition, the average trough concentration of tacrolimus significantly correlated with the logarithmically transformed MDR1 mRNA data from the blood cells in patients of both the event-free (r = 0.5406; P = 0.0077) and ACR (r = 0.4772; P = 0.0284). The cellular accumulation of [(14)C]tacrolimus in the peripheral blood mononuclear cells was 2-fold higher in mdr1a/1b-knockout mice than in wild-type mice (P = 0.0182). These results suggest that MDR1 in blood cells decreases the leukocytic concentration of tacrolimus, and it could be a useful marker to establish an individualized target concentration of tacrolimus to prevent ACR in pediatric patients after liver transplantation.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Goto
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kiuchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oike
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016031:Liver Transplantation; D019520:Living Donors; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000097:blood*; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016559:Tacrolimus