Abstract
Aim: Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition. Patients & methods: We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). Results: Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10-75). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated. Conclusion: This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations.
Original submitted 19 December 2014; Revision submitted 2 April 2015
References
- 1 . Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab. Pharmacokinet. 22(5), 328–335 (2007).
- 2 Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab. Dispos. 34(5), 836–847 (2006).
- 3 Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin. Pharmacol. Ther. 87(6), 721–726 (2010).
- 4 . Dosing equation for tacrolimus using genetic variants and clinical factors. Br. J. Clin. Pharmacol. 72(6), 948–957 (2011).
- 5 Validation of tacrolimus equation to predict troughs using genetic and clinical factors. Pharmacogenomics 13(10), 1141–1147 (2012).
- 6 . A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients. Br. J. Clin. Pharmacol. 76(3), 425–431 (2013).
- 7 . The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations. Br. J. Clin. Pharmacol. 75(6), 1545–1547 (2013).
- 8 Clinicaltrials.gov: NCT01714440 (2015). www.clinicaltrials.gov.
- 9 Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91(3), 300–308 (2011).
- 10 Lower calcineurin inhibitor doses in older compared with younger kidney transplant recipients yield similar troughs. Am. J. Transplant. 12(12), 3326–3336 (2012).
- 11 . A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68(4), 978–989 (2001).
- 12 . Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clin. Pharmacokinet. 52(9), 751–762 (2013).
- 13 . Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function. Pharmacogenomics J. 11(1), 25–34 (2011).
- 14 . Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase. J. Biol. Chem. 277(8), 6536–6541 (2002).
- 15 Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase. J. Biol. Chem. 278(28), 25895–25901 (2003).
- 16 Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase. J. Biol. Chem. 278(15), 13480–13486 (2003).
- 17 . Genetic and clinical features of p450 oxidoreductase deficiency. Horm. Res. 69(5), 266–275 (2008).
- 18 . Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism. Pharmacogenet. Genomics 18(1), 11–24 (2008).
- 19 . Pharmacogenetics of P450 oxidoreductase: implications in drug metabolism and therapy. Pharmacogenet. Genomics 22(11), 812–819 (2012).
- 20 P450 oxidoreductase (POR) allele nomenclature (2015). www.cypalleles.ki.se/por.htm.
- 21 . Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc. Natl Acad. Sci. USA 105(5), 1733–1738 (2008).
- 22 Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet. Genomics 20(11), 677–686 (2010).
- 23 . Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3. Pharmacogenet. Genomics 22(8), 590–597 (2012).
- 24 . Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase. Pharmacogenet. Genomics 20(10), 611–618 (2010).
- 25 Rapid determination of enzyme activities of recombinant human cytochromes P450, human liver microsomes and hepatocytes. Biopharm. Drug Dispos. 24(9), 375–384 (2003).
- 26 . Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-alpha are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet. Genomics 23(12), 649–657 (2013).
- 27 . The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test. Pharmacogenet. Genomics 19(11), 877–883 (2009).
- 28 . The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics 12(9), 1281–1291 (2011).
- 29 . Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. Eur. J. Clin. Pharmacol. 69(4), 807–812 (2013).
- 30 Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Ther. Drug Monit. 36(1), 71–79 (2014).
- 31 CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients. Ther. Drug Monit. 36(6), 710–715 (2014).
- 32 . Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. Pharmacogenet. Genomics 24(12), 597–606 (2014).
- 33 The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur. J. Clin. Pharmacol. 70(6), 685–693 (2014).
- 34 . Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 11(4), 274–286 (2011).
- 35 . CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes. J. Toxicol. Sci. 38(3), 349–354 (2013).
- 36 . The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients. Pharmacogenet. Genomics 22(5), 373–380 (2012).
- 37 A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clin. Chem. 57(11), 1574–1583 (2011).
- 38 Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors’ dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 12(10), 1383–1396 (2011).
- 39 . CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics 14(1), 47–62 (2013).
- 40 Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines. Ther. Drug Monit. 35(5), 608–616 (2013).
- 41 CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients. Pharmacogenomics 14(9), 1027–1036 (2013).
- 42 . CYP3A5 genotype, but not CYP3A4*1b, CYP3A4*22, or hematocrit, predicts tacrolimus dose requirements in Brazilian renal transplant patients. Clin. Pharmacol. Ther. 94(2), 201–202 (2013).
- 43 Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population. PLoS ONE 9(1), e83472 (2014).
- 44 Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation. CPT Pharmacometrics Syst. Pharmacol. 3, e100 (2014).
- 45 . Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin. Pharmacokinet. 49(3), 141–175 (2010).
- 46 . Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part II. Clin. Pharmacokinet. 49(4), 207–221 (2010).
- 47 . Expression and function of efflux drug transporters in the intestine. Pharmacol. Ther. 109(1–2), 137–161 (2006).
- 48 Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br. J. Pharmacol. 117(8), 1730–1734 (1996).
- 49 . Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82(8), 1074–1084 (2006).
- 50 Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am. J. Transplant. 5(5), 987–994 (2005).
- 51 Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics 10(4), 579–599 (2009).