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: 2.38). 12/2010; 32(6):708-14. DOI: 10.1097/FTD.0b013e3181f3c063
Source: PubMed


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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Available from: Arden R Barry, Jul 08, 2014
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    • "The CYP3A5 gene represents the major extrahepatic isoform of CYP3A gene family and in association with CYP3A4 are responsible for the metabolism of over 50% of all the clinically used drugs [9]. Some studies pay special attention at the frequent CYP3A5*3 allele and tacrolimus dosing [10], a frequently used immunosuppressant drug. It is recommended that homozygous CYP3A5*3/*3 patients receive roughly a 50% lower initial tacrolimus dose than patients with at least one wild type CYP3A5*1 allele as a result of the difference observed in oral clearance [10,11]. "
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    ABSTRACT: Two variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus. We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses. Our data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.
    BMC Research Notes 03/2014; 7(1):123. DOI:10.1186/1756-0500-7-123
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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 · 3.25 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: Current molecular tools lack the ability to differentiate the activity of CYP3A4 and CYP3A5 in biological samples such as human liver microsomes. Kinetic experiments and the CYP3A4 crystal structure indicate that the active sites of both enzymes are large and flexible, and have more than one binding subsite within the active site. 1-(4-Imidazopyridinyl-7phenyl)-3-(4'-cyanobiphenyl) urea (SR-9186) was optimized through several rounds of structural refinement from an initial screening hit to obtain greater than 1000-fold selectivity for the inhibition of CYP3A4 versus CYP3A5. Characterization data demonstrate selectivity using midazolam and testosterone hydroxylation assays with recombinant cytochrome P450, pooled human liver microsomes, and individually genotyped microsomes. Clear differences are seen between individuals with CYP3A5*1 and *3 genotypes. The antifungal drug ketoconazole is the most commonly used CYP3A inhibitor for in vitro and in vivo studies. A direct comparison of SR-9186 and ketoconazole under typical assay conditions used in reaction phenotyping studies demonstrated that SR-9186 had selectivity over CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A5 greater than or equal to that of ketoconazole. In addition, the long half-life (106 min) of SR-9186 in incubations containing 1 mg/ml human liver microsomes provided sustained CYP3A4 inhibition.
    Drug metabolism and disposition: the biological fate of chemicals 06/2012; 40(9):1803-9. DOI:10.1124/dmd.112.046144 · 3.25 Impact Factor
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