title: Influence of cytochrome P450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mRNA expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients.
abstract: Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital.
authors.forename: Miwa
authors.initials: M
authors.lastname: Uesugi
authors.forename: Mio
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinke
authors.forename: Emina
authors.initials: E
authors.lastname: Hashimoto
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.forename: Kohei
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.forename: Toshimi
authors.initials: T
authors.lastname: Kaido
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016559:Tacrolimus / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus