Drug-drug interactions of tacrolimus

Drug-drug interactions of tacrolimus A Nemanja K. Rančić1, Neven N. Vavić2, Aleksandra M. Kovačević1, Momir M. Mikov3, Viktorija M. Dragojević Simić1 A 1 Centre for Clinical Pharmacology, Medical Faculty of Military Medical Academy, University of Defence, Belgrade, Serbia 2 Centre for Transplantation of Solid Organs, Military Medical Academy, Belgrade, Serbia 3 Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, University of Novi Sad, Serbia A SUMMARY


INTRODUCTION
Tacrolimus is a macrolide immunosuppressant that is used to prevent organ rejection in patients with liver, kidney or heart graft s.It is a lipophilic drug with a narrow therapeutic window.Due to its physicochemical characteristics it is a subject of intensive metabolism and has highly variable absorbtion and, as a result of that, its main characteristics are variable pharmacokinetics [1][2][3][4].However, due to its potency, tacrolimus is widely used to prevent allograft rejection in the patients with transplanted organs or tissues [5].Due to all these facts, tacrolimus is the most common research drug subject in the transplantation area.

THE AIM
Th e aim of this current topic is to describe the importance of tacrolimus drug-drug interactions, as well as to present short review of such interactions.

PHARMACOKINETIC INTERACTIONS BETWEEN TACROLIMUS AND OTHER DRUGS
Tacrolimus absorption from the human gastrointestinal tract shows great variability.In some patients it is rapidly absorbed aft er oral administration (maximal blood concentration can be achieved in approximately 1 to 2 hours), while in others absorption time can be slower or even delayed.
Th e bioavailability of tacrolimus is low (about 20%) due to its extensive presystemic metabolism, but may vary between 4 to 93% [6,7].It is a substrate of P-glycoprotein doi:10.5937/hpimj1503291Reffl ux pump, which is one of the drug transporters that determine a range of its uptake and effl ux [8][9][10][11].
P-glycoprotein functions as a transmembrane effl ux pump, pumping substrates from the intracellular to extracellular space.Th is pump is presented in the intestinal epithelium, renal tubules epithelium, hepatocytes, blood-brain-barrier and placenta [12].Th erefore, tacrolimus bioavailability is largely determined by its pumping back into the intestinal lumen mediated by this effl ux transporter.P-glycoprotein inductors and inhibitors interact with tacrolimus through this pump (Table 1) [11,13].Some drugs, substrate of P-glycoprotein, may occupy active places of this pump, which may lead to higher tacrolimus absorption and bioavailability [9,11].On the other hand, the inhibition or induction of P-glycoprotin may produce the increased or decreased tacrolimus blood concentration, respectively.
Tacrolimus is metabolized in the liver by cytohrome P450 (CYP) [7].It is a substrate of both CYP3A4 and CYP3A5 enzymes.Gene polymorphisms of both CYP3A4 and CYP3A5 enzymes are signifi cant factor which contributes to its highly variable bioavailability [14][15][16][17][18]. Th erefore, tacrolimus large inter-and intra-individual pharmacokinetic variability could be at least partially explained by the genetic polymorphism of CYP3A genes.
Drug interactions with tacrolimus mediated by CYP3A enzymes, aff ecting its concentrations in blood are presented in Table 2 [19][20][21][22][23][24].CYP3A enzyme system inhibitors may lead to the increased tacrolimus blood concentrations, while its inducers may reduce them.Substrates of CYP3A enzyme system probably occupy them leading to increased tacrolimus blood concentrations.Overexposure to aforementioned substrates can results in signifi cant tacrolimus toxicity, while the subtherapeutic blood concentrations probably lead to the increased probability of organ rejection [22,25,26].Th e clinical signifi cance of the described interactions is very important.For example, interactions between tacrolimus and proton pump inhibitors (omeprazole and lansoprazole) are of clinical importance.Proton pump inhibitors are metabolized by cytochrome P450 enzymes, most prominently CY-P3A4 and CYP2C19 and they are also substrats of P-glycoprotein [27,28].Since tacrolimus and proton pump inhibitors share the affi nity Table 1.Drugs that interact with tacrolimus through P-glycoprotein effl ux pump for CYP3A4 enzymes and compete each other for these enzymes as well as for P-glycoprotein, drug interactions should be anticipated when these drugs are administrated simultaneously.Th erefore, combining these drugs leads to increased tacrolimus blood concentrations, since, as it was mentioned, omeprazole and lansoprazole are inhibitors and/or substrates of CYP3A4 enzymes and P-glycoprotein effl ux pump [27][28][29][30].
On the other hand, calcium channel blockers (diltiazem, nifedipine, amlodipine) are potent inhibitors and/or substrates of CY-P3A4 and CYP3A5 enzymes, as well as of Pglycoprotein transporter, and they can rapidly increase tacrolimus blood concentrations [31].Since calcium channel blockers decrease the clearance of tacrolimus by partial competative inhibiton of metabolic pathway, it leads to a signifi cantly elevated tacrolimus blood concentrations [32,33].

CONCLUSION
Tacrolimus drug-drug interactions mediated www.hophonline.orgTable 2. Drugs that interact with tacrolimus through CYP3A enzymes by both P-glycoprotein and CYP3A enzymes are potentially very important, concerning the narrow therapeutic range of this immunosuppressant and variable pharmacokinetics.Th erefore, relativelly small alterations in tacrolimus bioavailability and its metabolism, as a whole, may lead to the signifi cant increase or decrease of its blood level.Interactions with other drugs leading to overexposure of tacrolimus is connected with signifi cant toxicity, while the subtherapeutic blood concentrations lead to the increased probability of transplanted organ rejection.
Understanding the fundamental principles of tacrolimus drug-drug interactions could contribute to better transplant patients pharmacotherapy, especially concerning the fact that it is a long-term and expensive treatment associated with transplant rejection risk.

ACKNOWLEDGMENTS
Th e authors would like to express their gratitude to the Ministry of Science and Education Republic of Serbia for Grant numbers 175014 and 175093, out of which this research project was partially fi nanced.York: McGraw Hills Companies, Inc., 2010:939-64.24.Sweetman SC, ed.Martindale: The Complete Drug Reference 37. [CD-ROM] London: Pharmaceutical Press; 2011. www.hophonline.org