A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Therapeutic drug monitoring (Impact Factor: 1.93). 12/2010; 32(6):708-14. DOI: 10.1097/FTD.0b013e3181f3c063
Source: PubMed

ABSTRACT 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.

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    • "The immunosuppressant tacrolimus requires trough concentration to be maintained between 5 and 15 ng/ml. Patients who express active CYP3A5 (*1/*1 or *1/*3) require approximately twice the dose compared with *3/*3 patients to maintain an appropriate tacrolimus concentration (Zhao et al., 2005; Barry and Levine, 2010). The CYP3A5 genotype was also shown to be involved in drug-drug interactions caused by fluconazole, which inhibits CYP3A4 2 to 5 times more potently than CYP3A5. "
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    ABSTRACT: Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap and there is currently no way to selectively monitor the activity of these two enzymes individually, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, leading to individuals with large differences in CYP3A5 expression levels which have been shown to alter the pharmacokinetics of drugs in patients. We report the first highly selective CYP3A5 substrate, T-5, capable of determining CYP3A5 activity in biological samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N-oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N-oxide highly correlates with CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.
    Drug metabolism and disposition: the biological fate of chemicals 12/2013; 42(3). DOI:10.1124/dmd.113.054726 · 3.33 Impact Factor
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    • "A better understanding of both enzymes is important to make accurate clearance predictions before compounds are moved into human trials. The clinical relevance of the CYP3A5 genotype is seen with the immunosuppressant tacrolimus, which is metabolized by CYP3A5 3 times more efficiently than by CYP3A4 (Barry and Levine, 2010). To maintain the required tacrolimus trough concentrations of 5 to 15 ng/ml, patients who express active CYP3A5 (*1/*1 and *1/*3 genotypes) require approximately twice the dose as patients with the *3/*3 (inactive splice variant) genotype (Zhao et al., 2005). "
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    ABSTRACT: Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.
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