Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar


Am J Health Syst Pharm. 2006;63(23):2340-2348. 

In This Article

Abstract and Introduction


Purpose. The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined.
Summary. The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial.
Conclusion. For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25-45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.


During 2004, more than 27,000 solid-organ transplant surgeries were performed in the United States.[1] Of those, more than 16,000 were renal transplantations. The cornerstone of long-term survival after modern solid-organ transplantation is the use of pharmacologic agents for immunosuppression. Several drug classes have been used to successfully suppress the transplant recipient’s immune system, including corticosteroids, calcineurin inhibitors, antiproliferative agents, polyclonal anti-bodies, and monoclonal antibodies. The calcineurin inhibitors are a highly efficacious class of immunosuppressants for use following solid-organ transplantation[2] but are clinically difficult to use because of their narrow therapeutic range and highly variable pharmacokinetic profile.[3,4,5] The source of pharmacokinetic variability seen with the calcineurin inhibitors is not fully understood, and attempts to simplify the initiation and maintenance of these agents have been unsuccessful.

Pharmacogenetics examines the relationship between single-gene polymorphisms and the associated effects on the pharmacokinetics and pharmacodynamics of medications. Pharmacogenomics uses more complex models of genetic variability to analyze genetic composition and the corresponding effect on drug action in vivo. Analyzing the interactions of proteins and drugs in individuals with genetic polymorphisms may provide clinicians with another tool for making rational therapeutic decisions at a level of individual patient specificity. Specifically, pharmacogenomic analysis may prove to be useful in therapeutic regimens where the medications used have a narrow therapeutic range, a high cost, or significant adverse effects with sub-optimal use.

Calcineurin inhibitors are a class of medications with which the use of pharmacogenetics may be justified in predicting subsequent therapy because of their highly variable pharmacokinetcs, narrow therapeutic range, cost, and importance to the transplant recipient’s long-term survival. This article reviews the medical literature analyzing single-nucleotide polymorphism (SNP) genotypes of key metabolic enzymes and transport proteins with respect to their corresponding effects on the pharmacokinetics of calcineurin inhibitors.


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