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World J Gastroenterol. Dec 28, 2013; 19(48): 9156-9173
Published online Dec 28, 2013. doi: 10.3748/wjg.v19.i48.9156
Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients
Alessio Provenzani, Andrew Santeusanio, Erin Mathis, Monica Notarbartolo, Manuela Labbozzetta, Paola Poma, Ambra Provenzani, Carlo Polidori, Giovanni Vizzini, Piera Polidori, Natale D’Alessandro
Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy
Andrew Santeusanio, Erin Mathis, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States
Monica Notarbartolo, Manuela Labbozzetta, Paola Poma, Natale D’Alessandro, G. D’Alessandro Department of Health Promotion Sciences, Section of Pharmacology P Benigno, University of Palermo, 90127 Palermo, Italy
Ambra Provenzani, National Institute of Social Security (INPS), 90143 Palermo, Italy
Carlo Polidori, School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Giovanni Vizzini, Department of Medicine, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy
Author contributions: Provenzani A, Santeusanio A and Mathis E wrote the paper and contributed equally to this work; Notarbartolo M, Labbozzetta M, Poma P and Provenzani A reviewed the literature; Polidori C, Vizzini G and Polidori P reviewed the paper; D’Alessandro N provided critical expertise and reviewed the paper.
Correspondence to: Alessio Provenzani, PharmD, PhD, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), via E. Tricomi n. 5, 90127 Palermo, Italy. aprovenzani@ismett.edu
Telephone: +39-340-6046147 Fax: +39-91-2192369
Received: August 19, 2013
Revised: September 30, 2013
Accepted: October 19, 2013
Published online: December 28, 2013
Processing time: 148 Days and 4.3 Hours
Abstract

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Keywords: Pharmacogenetics; Calcineurin inhibitors; Tacrolimus; Liver transplant; Kidney transplant; Single nucleotide polymorphisms; CYP3A4; CYP3A5; ABCB1

Core tip: As researchers continue to evaluate the influence of single nucleotide polymorphisms on tacrolimus dosing and on the response to the drug, the challenge now becomes to assess the potential clinical implications of this research for medical practice. Sufficient data have been accumulated to be certain that the liver donor and kidney recipient CYP3A5 genotype has an important influence on tacrolimus dosing and on the observed blood trough levels of the drug. However, the question remains, should genotyping become a standard of practice in transplantation?