The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

[1]  Y. Touitou,et al.  Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant , 2020, Toxicology and Applied Pharmacology.

[2]  J. Fehr,et al.  The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study , 2019, Clinical pharmacology and therapeutics.

[3]  T. Hibi,et al.  Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis , 2019, Intestinal research.

[4]  A. Somogyi,et al.  Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation , 2019, Pharmacogenetics and genomics.

[5]  Hailing Qiao,et al.  Association of CYP3A4*1B genotype with Cyclosporin A pharmacokinetics in renal transplant recipients: A meta-analysis. , 2018, Gene.

[6]  A. Spinelli,et al.  Surgery in ulcerative colitis: When? How? , 2018, Best practice & research. Clinical gastroenterology.

[7]  LiuFei,et al.  Long-Term Influence of CYP3A5, CYP3A4, ABCB1, and NR1I2 Polymorphisms on Tacrolimus Concentration in Chinese Renal Transplant Recipients. , 2017 .

[8]  T. Shimosegawa,et al.  ATP‐binding cassette subfamily B member 1 1236C/T polymorphism significantly affects the therapeutic outcome of tacrolimus in patients with refractory ulcerative colitis , 2017, Journal of gastroenterology and hepatology.

[9]  L. Peyrin-Biroulet,et al.  Ulcerative colitis , 2017, The Lancet.

[10]  M. Hirata,et al.  Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium–Based Treatment in Brazilian Kidney Transplant Recipients , 2017, Pharmacotherapy.

[11]  O. Inatomi,et al.  The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. , 2017, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[12]  Na Gao,et al.  Physiological Content and Intrinsic Activities of 10 Cytochrome P450 Isoforms in Human Normal Liver Microsomes , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[13]  A. Ido,et al.  Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis. , 2016, Journal of Crohn's & colitis.

[14]  Y. Tanigawara,et al.  Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole , 2015, Journal of clinical pharmacology.

[15]  K. Aouam,et al.  Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase. , 2015, Pharmacogenomics.

[16]  A. Gayle,et al.  Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation , 2015, Therapeutic drug monitoring.

[17]  M. Huang,et al.  Interactive effects of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tracrolimus trough concentrations in early postrenal transplant recipients. , 2015, Pharmacogenomics.

[18]  Julia M. Barbarino,et al.  Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing , 2015, Clinical pharmacology and therapeutics.

[19]  Wei Zhang,et al.  CYP3A4*1G Genetic Polymorphism Influences Metabolism of Fentanyl in Human Liver Microsomes in Chinese Patients , 2015, Pharmacology.

[20]  K. Ohtsuka,et al.  Tacrolimus for the Treatment of Ulcerative Colitis , 2015, Intestinal research.

[21]  J. Qiu,et al.  The effect of CYP3A4*1G allele on the pharmacokinetics of atorvastatin in Chinese han patients with coronary heart disease , 2014, Journal of clinical pharmacology.

[22]  T. Matsui,et al.  Impact of CYP3A5 genetic polymorphisms on the pharmacokinetics and short‐term remission in patients with ulcerative colitis treated with tacrolimus , 2014, Journal of gastroenterology and hepatology.

[23]  S. Uemoto,et al.  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. , 2013, Biological & pharmaceutical bulletin.

[24]  M. Shimizu,et al.  CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes. , 2013, The Journal of toxicological sciences.

[25]  J. Barrett,et al.  Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis , 2013, Pharmacogenetics and genomics.

[26]  U. Christians,et al.  Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients , 2013, Clinical Pharmacokinetics.

[27]  Jie Lu,et al.  Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co–therapy , 2013, Nature Medicine.

[28]  G. Koren,et al.  Tacrolimus-induced nephrotoxicity and genetic variability: a review. , 2012, Annals of transplantation.

[29]  T. Habuchi,et al.  Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients. , 2011, Pharmacogenomics.

[30]  Yuangan Wu,et al.  Impact of CYP3A4*1G polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery. , 2011, Clinica chimica acta; international journal of clinical chemistry.

[31]  J. Qiu,et al.  A functional polymorphism in the CYP3A4 gene is associated with increased risk of coronary heart disease in the Chinese Han population. , 2011, Basic & clinical pharmacology & toxicology.

[32]  K. Verbeke,et al.  Tacrolimus Dose Requirements and CYP3A5 Genotype and the Development of Calcineurin Inhibitor-Associated Nephrotoxicity in Renal Allograft Recipients , 2010, Therapeutic drug monitoring.

[33]  T. Habuchi,et al.  Impact of the CYP 3 A 4 * 1 G polymorphism and its combination with CYP 3 A 5 genotypes on tacrolimus pharmacokinetics in renal transplant patients , 2009 .

[34]  J. Ellenberg,et al.  Use of the noninvasive components of the mayo score to assess clinical response in Ulcerative Colitis , 2008, Inflammatory bowel diseases.

[35]  B. Charpentier,et al.  Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. , 2008, Basic & clinical pharmacology & toxicology.

[36]  Zheng Jiao,et al.  Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients , 2008, European Journal of Clinical Pharmacology.

[37]  G. Tenderich,et al.  No association between single nucleotide polymorphisms and the development of nephrotoxicity after orthotopic heart transplantation. , 2008, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[38]  A. Griffiths,et al.  Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[39]  V. Haufroid,et al.  CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[40]  B. Vinet,et al.  Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients , 2006, Pharmacogenetics and genomics.

[41]  J. Goldstein,et al.  Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. , 2005, Pharmacogenomics.

[42]  R. Kim,et al.  Genetic variability in CYP3A5 and its possible consequences. , 2004, Pharmacogenomics.

[43]  T. Habuchi,et al.  Influence of CYP3A5 and MDR1 (ABCB1) Polymorphisms on the Pharmacokinetics of Tacrolimus in Renal Transplant Recipients , 2004, Transplantation.

[44]  S. Masuda,et al.  CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. , 2004, Pharmacogenetics.

[45]  Teruhiko Yoshida,et al.  Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population , 2004, Human mutation.

[46]  J. Hudson,et al.  The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. , 2001, Pharmacogenetics.

[47]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[48]  M. Lai,et al.  Novel mutations of CYP3A4 in Chinese. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[49]  H. Yamazaki,et al.  Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver microsomes. , 1994, Biochemical pharmacology.