INTRODUCTION
Tacrolimus is an effective immunosuppressant, and its use in liver
transplantation (LT) is well established.1 However,
the drug has a narrow therapeutic window, and its pharmacokinetics and
pharmacodynamics vary considerably at both intraindividual and
interindividual level; hence, establishing an empirical dosage regimen
may pose a challenge.2-4
As a result of recent advances in pharmacogenomics, several single
nucleotide polymorphisms in the intron 3 of cytochrome P450 (CYP )3A5 were identified and were shown to correlate with the
expression of the gene and enzymatic activity of the product it
encodes.4 The intra- and interindividual variability
in tacrolimus pharmacokinetics and pharmacodynamics is partly associated
with the polymorphism of the genes for cytochrome P450 enzymes,CYP3A4 and CYP3A5 , and the efflux transporter
P-glycoprotein (P-gp).4 Polymorphism at a cryptic
splice site may result in either the presence (expressor, *1/*1
and *1/*3 ) or absence (non-expressor, *3/*3 ) ofCYP3A5. 4 The frequencies of CYP3A5polymorphism differ depending on race,4,5 with the
CYP3A5 expressors (i.e., *1/*1 or *1/*3 ) and MDR1 C3435Twild-type C allele carriers (i.e., CC or CT ) being more
prevalent among Asians (51% and 62.1%, respectively) than in
Caucasians (10% and 43.4%, respectively).6
Several studies demonstrated that the expression of CYP3A5results in a lower tacrolimus exposure, and hence, CYP3A5expressors might require a higher dose of the drug than
non-expressors.2,3,7,8 While we still know little
about the effect of CYP3A5 genotype on patient performance
post-transplant, it has been shown to affect tacrolimus
pharmacokinetics. A once-daily extended-release formulation
(Advagraf®) has been approved in many countries since
2007. Several studies have demonstrated that in stable patients after
LT, conversion from twice-daily to once-daily tacrolimus was
well-tolerated, safe and convenient.9,10 However,
despite similar pharmacokinetics of the twice-daily and once-daily
tacrolimus, some patients experienced adverse events, including liver
dysfunction, after the conversion.11
To the best of our knowledge, none of the previous studies analyzed a
link between CYP3A5 polymorphism and the changes in tacrolimus
pharmacokinetics after conversion from the twice-daily regimen to a
once-daily formulation. Therefore, the aim of this study was to compare
the incidence of liver dysfunction in stable liver transplant
recipients, both CYP3A5 expressors and non-expressors, after
conversion to once-daily expanded-release tacrolimus
(Advagraf®), and to analyze the effect ofCYP3A5 genotype on the pharmacokinetics of both a twice-daily
regimen and a once-daily tacrolimus formulation.