Abstract
AIMS: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac](blood) ) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac](cells) ) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac](blood) and [Tac](cells) , (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac](cells) and clinical outcomes after kidney transplantation. METHODS: A total of 175 renal transplant recipients were prospectively followed. [Tac](blood) and [Tac](cells) were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. RESULTS: Correlations between [Tac](blood) and [Tac](cells) were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac](cells) /[Tac](blood) ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%-173.2%). Age, albumin and haematocrit correlated with the [Tac](cells) /[Tac](blood) ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac](blood) and [Tac](cells) . ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac](blood) nor [Tac](cells) correlated with clinical outcomes. CONCLUSIONS: The correlation between [Tac](blood) and [Tac](cells) is poor. Age, albumin and haematocrit correlate with the [Tac](cells) /[Tac](blood) ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac](blood) nor [Tac](cells) correlated with clinical outcomes.