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Project

Pharmacogenetic Determinants of Tacrolimus Disposition and the Effects in Renal Transplant Organs and Recipients

The success of kidney transplantation is largely carried by the efficacy of CNIs. Until now no new immunosuppressive drugs have performed better than tacrolimus in large randomized trials. Because of its success, it will be difficult setting up trials with a sufficient number of patients and duration of follow-up to find new CNI-free immunosuppressive regimes with a superior long-term outcome. Nevertheless, tacrolimus is not a drug easy to use, especially because of the combination of large intra-and interindividual pharmacokinetic variation with a narrow therapeutic index, in both of which genetic variation appears to play an important role. Genetic variation also contributes to the interindividual variation in the occurrence of tacrolimus-related side effects under standard immunosuppressive treatment protocols, but little attention has been paid to the underlying mechanisms.

 

As long as no new alternatives for tacrolimus are likely to take its place, we should put more effort in understanding the effects of this drug in the individual patient and provide a tailored treatment to optimize outcome. This entails that we have to construct an integrative approach, “from gut to kidney”, of all the potential determinants of tacrolimus pharmacokinetics and dynamics in function of the renal allograft recipient and in the renal allograft itself. In particular clinical factors that affect the functional capacity of the gut-liver axis, ischemia-reperfusion injury, systemic inflammation, altered volume of distribution, decreased protein binding and certain co-medication (e.g. corticosteroids, antivirals) have to be taken into account (Chapter 2 of thesis). In children, this also includes the consideration of significant age-related effects on tacrolimus metabolism, which appears to be regulated by the same processes involved in bone maturation during puberty (Chapter 3). However, in the background the consequences of genetic variation in our xenobiotic defence system (in particular CYP3A5) play a dominant role in determining the right tacrolimus dose to reach the desired level of systemic exposure in the blood.

 

Despite similar systemic exposure levels important variation in long-term outcome associated with CNI nephrotoxicity remains. From a pharmacodynamics point of view systemic blood levels are not ideal and demonstrate a relatively variable correlation with tissue concentrations and pharmacodynamic parameters . We show that the in vitro exposure of proximal tubule cells to a range of concentrations associated with in vivo tissue levels (at similar systemic exposure) results in the production of profibrotic cytokines in a concentration dependent manner (Chapter 6). This profibrotic response was most pronounced in the cells with a pharmacogenetic background, associated with a lesser capacity for tacrolimus degradation and extrusion (Chapter 4 and 5). 

Date:1 Oct 2010 →  25 Oct 2017
Keywords:tacrolimus, metabolism
Disciplines:Urology and nephrology
Project type:PhD project