Korean J Transplant.  2020 Mar;34(1):24-30. 10.4285/kjt.2020.34.1.24.

Effect of cytochrome P450 3A5 polymorphism on the pharmacokinetics of tacrolimus in renal transplant recipients

• Htun YY
• Than NN
• Swe HK

• KMID: 2503779
• DOI: http://doi.org/10.4285/kjt.2020.34.1.24

Abstract

Background
Renal transplant is an effective treatment option for end-stage kidney disease and tacrolimus is one of the most commonly used immunosuppressant drugs in renal transplant patients. Tacrolimus is a substrate of cytochrome P450 3A5 (CYP3A5), and a narrow therapeutic index and large inter-individual variability. The objective of this study was to determine the frequency of CYP3A5*3 polymorphism and its effect on the pharmacokinetics of tacrolimus in post-renal transplant patients at Mandalay General Hospital.
Methods
Three different genotypes of CYP3A5 were determined by polymerase chain reaction-restriction fragment length polymorphism in 54 post-renal transplant recipients. Tacrolimus trough concentrations (Ctrough) were measured by enzyme multiplied immunoassay technique following method validation. The apparent clearance (CL/F) was calculated from measured Ctrough.
Results
The frequency of CYP3A5*1 allele was 0.24 and that of CYP3A5*3 allele was 0.76 in the study sample. There were a total of 33 CYP3A5 non-expressors (patients with CYP3A5*3/*3 genotype) and 21 CYP3A5 expressors (patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotype), respectively. CL/F was significantly lower in the non-expressor group than in the expressor group (mean±standard deviation, 12.53±5.28 vs. 21.22±5.95 L/hr; P<0.001). The mean Ctrough and concentration dose ratio (C/D) for tacrolimus in CYP3A5 non-expressors were significantly higher than those in CYP3A5 expressors (Ctrough, 7.14±2.56 vs. 5.92±1.76 ng/mL; C/D, 6.92±4.11 vs. 2.89±1.85 ng/mL/mg), respectively (P<0.05).
Conclusions
In this study, 76% of the Myanmar renal transplant recipients carried the CYP3A5*3 allele that was associated with lower functional activity of the CYP3A5 enzyme a lower CL/F of tacrolimus in these Thus, CYP3A5 polymorphism influences the pharmacokinetics of tacrolimus, which may affect the pharmacological response to tacrolimus.

Keyword

Tacrolimus; Pharmacokinetics; CYP3A5*3 polymorphism; Renal transplant recipients

Figure

• 

  Fig. 1 Frequency (%) of CYP3A5*1 and CYP3A5*3 allele in renal transplant recipients (Myanmar ethnics, n=54).

• 

  Fig. 2 (A) Comparison of mean trough concentration of tacrolimus between CYP3A5 non-expressor and expressor. (B) Comparison of mean tacrolimus concentration dose ratio (C/D) between CYP3A5 non-expressor and expressor. (C) Comparison of mean apparent clearance (CL/F) of tacrolimus between CYP3A5 non-expressor and expressor.

Reference

Patel DD., Modi KP., Patel AK. 2015. Prescription trends of immunosuppressant drugs in Indian renal transplant patients. Int J Pharm Sci Drug Res. 7:334–9.

Staatz CE., Goodman LK., Tett SE. 2010. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet. 49:141–75. DOI: 10.2165/11317350-000000000-00000. PMID: 20170205.

Chen L., Prasad GVR. 2018. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. Pharmgenomics Pers Med. 11:23–33. DOI: 10.2147/PGPM.S107710. PMID: 29563827. PMCID: PMC5846312.

Chan-On C., Sarwal MM. 2017. A comprehensive analysis of the current status and unmet needs in kidney transplantation in Southeast Asia. Front Med (Lausanne). 4:84. DOI: 10.3389/fmed.2017.00084. PMID: 28691007. PMCID: PMC5481314.

Shi WL., Tang HL., Zhai SD. 2015. Effects of the CYP3A4*1B genetic polymorphism on the pharmacokinetics of tacrolimus in adult renal transplant recipients: a meta-analysis. PLoS One. 10:e0127995. DOI: 10.1371/journal.pone.0127995. PMID: 26039043. PMCID: PMC4454552.

Hu YF., He J., Chen GL., Wang D., Liu ZQ., Zhang C, et al. 2005. CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population. Clin Chim Acta. 353:187–92. DOI: 10.1016/j.cccn.2004.11.005. PMID: 15698606.

Hustert E., Haberl M., Burk O., Wolbold R., He YQ., Klein K, et al. 2001. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 11:773–9. DOI: 10.1097/00008571-200112000-00005. PMID: 11740341.

Kuehl P., Zhang J., Lin Y., Lamba J., Assem M., Schuetz J, et al. 2001. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 27:383–91. DOI: 10.1038/86882. PMID: 11279519.

Provenzani A., Santeusanio A., Mathis E., Notarbartolo M., Labbozzetta M., Poma P, et al. 2013. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol. 19:9156–73. DOI: 10.3748/wjg.v19.i48.9156. PMID: 24409044. PMCID: PMC3882390.

Lamba J., Hebert JM., Schuetz EG., Klein TE., Altman RB. 2012. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics. 22:555–8. DOI: 10.1097/FPC.0b013e328351d47f. PMID: 22407409. PMCID: PMC3738061.

Jada SR., Xiang X., Zhou Q., Li HH., Ooi LL., Chowbay B. 2006. Hepatic expression of CYP3A4 and CYP3A5 genes in Asians and implications for pharmacokinetic variations during chemotherapy. J Clin Oncol. 24(18 Suppl):13124. DOI: 10.1200/jco.2006.24.18_suppl.13124.

Barry A., Levine M. 2010. A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. Ther Drug Monit. 32:708–14. DOI: 10.1097/FTD.0b013e3181f3c063. PMID: 20864901.

Zhou Y., Ingelman-Sundberg M., Lauschke VM. 2017. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin Pharmacol Ther. 102:688–700. DOI: 10.1002/cpt.690. PMID: 28378927. PMCID: PMC5600063.

Bergmann TK., Hennig S., Barraclough KA., Isbel NM., Staatz CE. 2014. Population pharmacokinetics of tacrolimus in adult kidney transplant patients: impact of CYP3A5 genotype on starting dose. Ther Drug Monit. 36:62–70. DOI: 10.1097/FTD.0b013e31829f1ab8. PMID: 24089074.

Boudia F., Boughrara W., Meriem A., Moghtit FZ., Hamdani A., Fetati H, et al. 2016. Effects of CYP3A5 and ABCB1 genetics variant on tacrolimus pharmacokinetics in Algerian adult renal transplant patients. J Med Sci Clin Res. 04:10182–8. DOI: 10.18535/jmscr/v4i4.34.

Spierings N., Holt DW., MacPhee IA. 2013. CYP3A5 genotype had no impact on intrapatient variability of tacrolimus clearance in renal transplant recipients. Ther Drug Monit. 35:328–31. DOI: 10.1097/FTD.0b013e318289644d. PMID: 23666583.

Htun YY., Swe HK., Saw TM. 2018. CYP3A5*3 genetic polymorphism and tacrolimus concentration in myanmar renal transplant patients. Transplant Proc. 50:1034–40. DOI: 10.1016/j.transproceed.2018.02.032. PMID: 29731062.

Rodriguez S., Gaunt TR., Day IN. 2009. Hardy-Weinberg equilibrium testing of biological ascertainment for mendelian randomization studies. Am J Epidemiol. 169:505–14. DOI: 10.1093/aje/kwn359. PMID: 19126586. PMCID: PMC2640163.

Hu R., Barratt DT., Coller JK., Sallustio BC., Somogyi AA. 2018. CYP3A5*3 and ABCB1 61A>G significantly influence dose-adjusted trough blood tacrolimus concentrations in the first three months post-kidney transplantation. Basic Clin Pharmacol Toxicol. 123:320–6. DOI: 10.1111/bcpt.13016. PMID: 29603629.

Zhang X., Liu ZH., Zheng JM., Chen ZH., Tang Z., Chen JS, et al. 2005. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 19:638–43. DOI: 10.1111/j.1399-0012.2005.00370.x. PMID: 16146556.

Min SI., Kim SY., Ahn SH., Min SK., Kim SH., Kim YS, et al. 2010. CYP3A5 *1 allele: impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation. 90:1394–400. DOI: 10.1097/TP.0b013e3181fa93a4. PMID: 21076384.

Roy JN., Barama A., Poirier C., Vinet B., Roger M. 2006. Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet Genomics. 16:659–65. DOI: 10.1097/01.fpc.0000220571.20961.dd. PMID: 16906020.

Chen JS., Li LS., Cheng DR., Ji SM., Sun QQ., Cheng Z, et al. 2009. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc. 41:1557–61. DOI: 10.1016/j.transproceed.2009.01.097. PMID: 19545678.

Rojas L., Neumann I., Herrero MJ., Bosó V., Reig J., Poveda JL, et al. 2015. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 15:38–48. DOI: 10.1038/tpj.2014.38. PMID: 25201288.

Cheng Y., Li H., Meng Y., Liu H., Yang L., Xu T, et al. 2015. Effect of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus and acute rejection in renal transplant recipients: experience at a single centre. Int J Clin Pract Suppl. (183):16–22. DOI: 10.1111/ijcp.12662. PMID: 26177012.

Li Y., Yan L., Shi Y., Bai Y., Tang J., Wang L. 2015. CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients. Springerplus. 4:637. DOI: 10.1186/s40064-015-1425-5. PMID: 26543771. PMCID: PMC4628029.

Suzuki Y., Homma M., Doki K., Itagaki F., Kohda Y. 2008. Impact of CYP3A5 genetic polymorphism on pharmacokinetics of tacrolimus in healthy Japanese subjects. Br J Clin Pharmacol. 66:154–5. DOI: 10.1111/j.1365-2125.2008.03162.x. PMID: 18341670. PMCID: PMC2485247.

Fitzsimmons WE., Bekersky I., Dressler D., Raye K., Hodosh E., Mekki Q. 1998. Demographic considerations in tacrolimus pharmacokinetics. Transplant Proc. 30:1359–64. DOI: 10.1016/S0041-1345(98)00275-9. PMID: 9636552.

Passey C., Birnbaum AK., Brundage RC., Oetting WS., Israni AK., Jacobson PA. 2011. Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. 72:948–57. DOI: 10.1111/j.1365-2125.2011.04039.x. PMID: 21671989. PMCID: PMC3244642.

Bauer LA. Bauer LA, editor. 2008. Immunosuppressants. Applied clinical pharmacokinetics. 3rd ed. McGraw-Hill Medical;New York, NY: p. 682–711.