A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients.
Tacrolimus is a commonly used immunosuppressive agent in renal transplantation. Therapeutic drug monitoring of tacrolimus is recommended because it demonstrates wide pharmacokinetic interpatient variability. Part of that variability may be the result of metabolism by cytochrome P450 3A5 (CYP3A5), which is only expressed in some adult individuals. The expression of CYP3A5 has been linked to the CYP3A5 genotype, in which individuals with one or more wild-type allele (CYP3A5*1) are considered CYP3A5 expressors, and individuals homozygous for the mutant allele CYP3A5*3 are considered nonexpressors. An association has been established between CYP3A5 genotype (expressors versus nonexpressors) and tacrolimus dose requirements to achieve target concentrations. Tacrolimus pharmacokinetic variability is based on bioavailability and systemic clearance, which are represented by apparent oral clearance. The focus of this review was to use a systematic method to investigate whether the CYP3A5 genotype has an effect on the apparent oral clearance of tacrolimus in renal transplant recipients. A total of five studies were identified that reported apparent oral clearance in CYP3A5 expressors and CYP3A5 nonexpressors. The weighted mean apparent oral clearance was found to be 48% lower in CYP3A5 nonexpressors than CYP3A5 expressors (range, 26%-65%). This difference in apparent oral clearance could be used in future studies to guide initial dosing strategies of tacrolimus in renal transplant recipients based on genotype.
Barry
Arden
A
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Levine
Marc
M
D019540:Area Under Curve; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000502:physiology; D016903:Drug Monitoring; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008657:Metabolic Clearance Rate; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus