From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation
DOI: 10.1016/j.ijpharm.2013.05.033
Title: From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation
Journal Title: International Journal of Pharmaceutics
Volume: 452
Publication Date: 16 August 2013
Start Page: 14
End Page: 35
Published online: online 24 May 2013
ISSN: 0378-5173

  • a Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Belgium

  • b Laboratory for Pediatrics, Department of Development & Regeneration, KU Leuven, Belgium

  • c Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium
  • Abstract: eir introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI's possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function, and food intake, but also graft-related characteristics such as: size, donor-age, and time after transplantation can be important. Fundamental (in vitro) and clinical studies have pointed out the intrinsic relation between the aforementioned variables and the functional capacity of enzymes and transporters involved in CNI metabolism, primarily located in intestine, liver and kidney. Commonly occurring polymorphisms in genes responsible for CNI metabolism (CYP3A4, CYP3A5, CYP3A7, PXR, POR, ABCB1 (P-gp) and possibly UGT) are able to explain an important part of interindividual variability. In particular, a highly prevalent SNP in CYP3A5 has proven to be an important determinant of CNI dose requirements and drug-dose-interactions. In addition, a discrepancy in genotype between graft and receptor has to be taken into account. Furthermore, common phenomena in solid organ transplantation such as inflammation, ischemia- reperfusion injury, graft function, co-medication, altered food intake and intestinal motility can have a differential effect on the expression enzymes and transporters involved in CNI metabolism. Notwithstanding the built-up knowledge, predicting individual CNI pharmacokinetics and dose requirements on the basis of current clinical and experimental data remains a challenge.
    Accepted: 10 May 2013
    Received: 8 March 2013
    Revised: 8 May 2013
    Keywords: Calcineurin-inhibitors; Tacrolimus; Cyclosporine; CYP3A5; CYP3A4; P glycoprotein
    Abbreviations: CNI, calcineurin-inihibitors; CsA, cyclosporine A; CNIT, CNI related nephrotoxicity; CN, calcineurin; NFAT, nuclear factor of activated T cells; Vd, volume of distribution; AUC, area under the concentration curve; BCS, Biopharmaceutics Classification System; DHA, Docosahexaenoic acid; SNP, single nucleotide polymorphism; TDM, therapeutic drug monitoring; CMPF, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid; IRI, ischemia-reperfusion-injury.
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