Influence of the Cyp3a5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients

Abstract

CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post-transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A5*3/*3). Therefore, a two-fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures ANOVA: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A5*1/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele-effect was correlated with one of the most common TAC side-effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre-emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…[17] Other investigators have also reported that CYP3A5 expressers do not have a higher risk of developing acute rejection. [18][19][20][21][22][23][24][25][26] Although numerous studies have reported the higher Tac dose requirement of CYP3A5 expressers compared to nonexpressers, the clinical relevance of this association is unclear and has so far only been investigated in two randomized-controlled clinical trials (RCT). The Tactique study [27] was a multicenter RCT, including 280 renal transplant recipients.…”

Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B5

“…Individuals expressing CYP3A5 may have higher clearance and lower bioavailability of CYP3A substrates compared with individuals not expressing CYP3A5 (Kuehl et al, 2001). This has been demonstrated for both the immunosuppressive drug tacrolimus and for several HMG-CoA reductase inhibitors (statins) where patients expressing CYP3A5 need higher drug dosages to reach target serum concentration or to achieve sufficient lipid-lowering response, respectively (Hesselink et al, 2003;Zheng et al, 2003;Goto et al, 2004; Kivisto et al, 2004;Ferraresso et al, 2007). CYP3A4 and CYP3A5 overlap in substrate specificity, but the relative importance of CYP3A4 and CYP3A5 in overall CYP3A-mediated metabolism differs between substrates .…”

Decreased Tacrolimus Levels after Administration of Rifampin to a Patient with Renal Transplant

“…CYP3A5*1 allele carriers ("high expressors") are known to require larger doses of tacrolimus to reach target blood concentrations than homozygous carriers of the CYP3A5*3 allele ("low expressors"). [3][4][5][6] In addition, CYP3A5 "high expressors" may require a longer period (up to 2 weeks) to achieve target blood concentrations than CYP3A5 "low expressors". 4 Macphee and others 4 reported lower tacrolimus concentrations in CYP3A5 "high expressors" during the first 2 weeks after renal transplant, despite therapeutic drug monitoring, and a significant delay in the time to reach target tacrolimus concentrations relative to CYP3A5 "low expressors".…”

“…1,2 Previous studies have shown that carriers of the CYP3A5*1 allele require larger doses of tacrolimus to achieve target blood concentrations than patients with other alleles. [3][4][5][6] The frequency of this allele varies depending on ethnicity and is more common among Asian and African American people than among whites. 7 Rifampin is known to affect the metabolism of tacrolimus through induction of CYP3A4 8 and, to a far lesser extent, CYP3A5.…”