CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

Abstract

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

Effect of Tacrolimus Formulation (Prolonged‐Release vs Immediate‐Release) on Its Susceptibility to Drug‐Drug Interactions with St. John's Wort

“…38 The extent of CYP3A5 activity in the colon is unclear, but recent data are in line with a significant role of CYP3A5 in tacrolimus intestinal firstpass elimination also in the colon. 39 Consistently, in our trial, tacrolimus exposure with PR-Tac was also lower in CYP3A5 expressors than in non-expressors (Table S12). This is more likely explained by higher intestinal first-pass elimination because comparable terminal half-life in both groups (Table S12) indicates that systemic elimination does not seem affected by CYP3A5 genotype.…”

“…A possible explanation could be that in expressors, CYP3A4 and CYP3A5 both contribute to tacrolimus metabolism and induction of CYP3A4 by SJW, if present, results in the same absolute increase in CYP3A activity in both expressors and non‐expressors but the relative increase in CYP3A activity is smaller in CYP3A5 expressors when CYP3A5 is not induced by SJW, as suggested by in vitro data 38 . The extent of CYP3A5 activity in the colon is unclear, but recent data are in line with a significant role of CYP3A5 in tacrolimus intestinal first‐pass elimination also in the colon 39 . Consistently, in our trial, tacrolimus exposure with PR‐Tac was also lower in CYP3A5 expressors than in non‐expressors (Table S12).…”

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

“…These autoimmune diseases responsible genes might be critical for the development of CD. Recently, study found that CXCL5 [454], S100A12 [455], OSM (oncostatin M) [456], LRG1 [457], LCN2 [458], CXCL1 [459], S100A9 [460], IFITM1 [461], XBP1 [462], MMP3 [457], IFITM3 [463], IL1B [464], GBP5 [465], HGF (hepatocyte growth factor) [466], CXCL9 [467], SLC11A1 [468], IL1RN [469], STAT1 [470], CYP27B1 [471], MMP1 [472], SOCS3 [473], TLR8 [474], CD55 [475], CCL28 [476], FCGR2A [477], CCL2 [478], CFB (complement factor B) [479], CD14 [480], GPR84 [481], PCSK9 [482], FOXP3 [483], LPL (lipoprotein lipase) [484], IL1R2 [485], TLR2 [486], MEFV (MEFV innate immuity regulator, pyrin) [487], VWF (von Willebrand factor) [488], NOD2 [489], DMBT1 [490], HSPA6 [491], TIMP1 [492], ICAM1 [493], EGR1 [494], CCL11 [495], IFNG (interferon gamma) [496], APOE (apolipoprotein E) [497] FGR (FGR proto-oncogene, Src family tyrosine kinase) [498], IL6 [499], SPP1 [192], IL11 [500], RNF186 [501], MMP2 [502], CD24 [503], SPHK1 [504], GZMB (granzyme B) [505], MUC5AC [506], SERPINA3 [507], TWIST1 [508], PLAU (plasminogen activator, urokinase) [509], CA2 [510], CA9 [510], CTLA4 [511], PADI4 [512], MMP13 [513], MPO (myeloperoxidase) [244], LEFTY1 [514], CA1 [515], MMP7 [513], ABCG2 [516], CYP2J2 [517], AICDA (activation induced cytidine deaminase) [518], CYP2D6 [519], CYP3A5 [52...…”

Renal and Urological Disorders Associated With Inflammatory Bowel Disease

“…67 Yamamoto et al found that the tacrolimus dose to maintain equivalent blood concentrations was lower in patients carrying the cytochrome (CYP) 3A5*3/*3 than in those carrying the CYP3A5*1 genotype, and the concentration/dose ratio was significantly higher in the latter. 68 Ciclosporin is an option for treating acute severe UC, but it has a significant toxicity profile, with nephrotoxicity occurring in 6.3%. 7,69 Rat models have revealed that acute renal damage secondary to ciclosporin is due to vasoconstriction of the afferent arterioles, leading to diminished renal blood flow and glomerular filtration, with a consequent rise in serum creatinine.…”