title: Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation.
abstract: We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 +/- 125.3 (average +/- SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 +/- 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 +/- 385.4 mg/d, average +/- SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Maki
authors.initials: M
authors.lastname: Goto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kiuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kodawara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D002908:Chronic Disease; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D020895:Enterocytes / Q000502:physiology*; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D016559:Tacrolimus / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus