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Tacrolimus Elimination in Four Patients With a CYP 3A5*3/*3 CYP 3A4*22/*22 Genotype Combination
Author(s) -
Scheibner Aileen,
Remmel Rory,
Schladt David,
Oetting William S.,
Guan Weihua,
Wu Baolin,
Dorr Casey,
Israni Ajay,
Jacobson Pamala A.
Publication year - 2018
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.2131
Subject(s) - tacrolimus , cyp3a4 , cyp3a5 , genotype , cyp3a , biology , pharmacology , cytochrome p450 , medicine , transplantation , endocrinology , metabolism , genetics , gene
Cytochrome P450 3A5 ( CYP 3A5) and cytochrome P450 3A4 ( CYP 3A4) are the predominate enzymes responsible for tacrolimus metabolism. The presence of CYP 3A4 and CYP 3A5 genetic variants significantly affects tacrolimus clearance and dose requirements. CYP 3A5*3 is a loss‐of‐function variant resulting in no CYP 3A5 enzyme production. CYP 3A4*22 is a variant that reduces production of functional CYP 3A4 protein. Caucasians commonly carry these variant alleles but are very rarely homozygous for both CYP3A5*3 and CYP3A4*22 . This report describes four kidney transplant recipients who carry a rare genotype combination ( CYP 3A5*3/*3 and CYP 3A4*22/*22 ). These patients were identified from a larger cohort of Caucasian kidney transplant recipients (n=1366). To understand the significance of this genotype combination on tacrolimus troughs and doses, we compared these patients to recipients without this combination. Patients homozygous for both variants are at risk for profound reductions in metabolism of CYP 3A substrates. A 342% and a 90.6% increase in the median dose‐normalized trough was observed, when the CYP3A5*3/*3 and CYP3A4*22/*22 genotype combination was compared to the CYP3A5*1/*1 and CYP3A4*1/*1 genotype combination and the CYP3A5*3/*3 and CYP3A4*1/*1 genotype combination, respectively. These four individuals only required on average 2.5 mg/day of tacrolimus. Knowledge of these genotypes would be useful in selecting appropriate tacrolimus doses to avoid overexposure.