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.