HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Utecht, K. N. Articles by Kolesar, J. Search for Related Content PubMed PubMed Citation Articles by Utecht, K. N. Articles by Kolesar, J.

KYLE N. UTECHT is a Pharm.D. degree candidate; JON J. HILES is a Pharm.D. degree candidate; and JILL KOLESAR, PHARM.D., is Associate Professor, School of Pharmacy, University of Wisconsin, Madison.

Address correspondence to Dr. Kolesar at K4/544 Clinical Sciences Center, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792 (jmkolesar{at}pharmacy.wisc.edu).

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. Index terms: Blood levels; Cyclosporine; Dosage; Drugs, availability; Graft rejection; Immunosuppressive agents; Metabolism; Pharmacogenetics; Pharmacokinetics; Polymorphism; Tacrolimus; Toxicity; Transplantation

 

This article has been cited by other articles:

				S. De Fazio, L. Gallelli, A. De Siena, G. De Sarro, and M. G. Scordo Role of CYP3A5 in Abnormal Clearance of Methadone Ann. Pharmacother., June 1, 2008; 42(6): 893 - 897. [Abstract] [Full Text] [PDF]