Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients.
It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CYP3A5*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.
Uesugi
Miwa
M
Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Shogoin, Kyoto, Japan.
Masuda
Satohiro
S
Katsura
Toshiya
T
Oike
Fumitaka
F
Takada
Yasutsugu
Y
Inui
Ken-ichi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D016031:Liver Transplantation / Q000379:methods*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D016559:Tacrolimus / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus