title: Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients.
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.
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Andrew
authors.initials: A
authors.lastname: Santeusanio
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Erin
authors.initials: E
authors.lastname: Mathis
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Notarbartolo
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Labbozzetta
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Poma
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Ambra
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Polidori
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vizzini
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Polidori
authors.affiliation: Alessio Provenzani, Piera Polidori, Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy.
authors.forename: Natale
authors.initials: N
authors.lastname: D'Alessandro
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D054796:Drug Dosage Calculations; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000009:adverse effects; D016031:Liver Transplantation / Q000009:adverse effects; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: ABCB1; CYP3A4; CYP3A5; Calcineurin inhibitors; Kidney transplant; Liver transplant; Pharmacogenetics; Single nucleotide polymorphisms; Tacrolimus