Date: Tuesday, June 5, 2018
Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Location: Room 6C
Purpose: Tacrolimus (TAC) is a well-known cytochrome P450 (CYP) 3A4 and 3A5 substrate. Common single nucleotide polymorphisms (SNPs) in these genes are significantly related to variation in TAC pharmacokinetics and dose-requirements. The CYP3A5*3 allele is a common loss of function variant (splice junction variant) and the CYP3A4*22 allele dramatically reduces production of functional CYP3A4 protein. The purpose of the study was to identify TAC metabolism in individuals homozygous for mutations in both the CYP3A4 and 3A5 genes relative to patients carrying one or more functional alleles in each of these genes. Methods. We studied 1366 Caucasian kidney transplant recipients taking oral tacrolimus enrolled in the DeKAF Genomics study. A median of 17 TAC troughs were obtained each patient in the first 6 months posttx. Patients were categorized into 6 groups based on CYP3A5*3 and CYP3A4*22 variants and compared. Results: Four subjects were found that carried a rare genotype combination (CYP3A5*3/*3 and CYP3A4*22/*22) and had 3-fold higher dose-normalized TAC troughs and 3-fold lower doses requirements than those not carrying these variants. Based on genotype we predicted that these subjects would have little to no metabolic activity towards TAC but yet they demonstrated the ability to metabolize, albeit much reduced. Conclusion: These data suggest that either the CYP3A4*22 allele is not a complete loss of function and expresses sufficient CYP3A4 protein for TAC metabolism or there is alternative TAC metabolism pathways outside of the CYP3A enzyme that contributes to clearance in patients homozygous for these variants.
CITATION INFORMATION: Scheibner A., Remmel R., Schladt D., Oetting W., Guan W., Wu B., Door C., Israni A., Jacobson P. Tacrolimus Metabolism in Subjects with Potentially Absent CYP3A Activity Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Scheibner A, Remmel R, Schladt D, Oetting W, Guan W, Wu B, Door C, Israni A, Jacobson P. Tacrolimus Metabolism in Subjects with Potentially Absent CYP3A Activity [abstract]. https://atcmeetingabstracts.com/abstract/tacrolimus-metabolism-in-subjects-with-potentially-absent-cyp3a-activity/. Accessed August 14, 2020.
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