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 multicentre European conversion study of 1832 RTRs mandated an increase ratio of 1 mg of Tac BID to 1.1 mg of Tac OD in participants with[. This is consistent with previous research on both adult and paediatric populations, reporting that expressers require higher doses of tacrolimus, due to higher oral clearance[14,15]. It was demonstrated that the *1/*3 expressers and the combined *1/*3 and *1/*1 expressers required significantly higher doses of Tac-OD after conversion from Tac-BID. "
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    ABSTRACT: Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C 0 ] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD. A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C 0 ] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA. Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C 0 ]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort. The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements. Trial registration Clinical identifier: NCT01884480
    Full-text · Article · Dec 2016
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    • "Few studies have examined the relationship between the CYP3A5 polymorphism and tacrolimus level in liver transplant patients. Moreover, the findings from these studies are inconsistent: some results showed that the receptor genotype has important implications for the metabolism of tacrolimus (Li et al., 2013; Spierings et al., 2013; Zhang et al., 2013), while other studies showed that blood tacrolimus level is more closely associated with the donor genotype (Barry and Levine, 2010; De Jonge et al., 2012; Valente et al., 2013). Thus, we performed a prospective study to identify the genotype with the most significant effect on tacrolimus metabolism. "

    Preview · Article · Jan 2015 · Genetics and molecular research: GMR
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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.
    Full-text · Article · Mar 2014 · BMC Research Notes
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