Article

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: 2.43). 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.

2 Bookmarks
 · 
104 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metabolism by cytochrome P4503A (CYP3A) is the most prevalent clearance pathway for drugs. Designation of metabolism by CYP3A commonly refers to the potential contribution by one or both of two enzymes, CYP3A4 and CYP3A5. The metabolic turnover of thirty-two drugs known to be largely metabolized by CYP3A was examined in HLM from CYP3A5 expressers (*1/*1 genotype) and non-expressers (*3/*3 genotype) in the presence and absence of ketoconazole and CYP3cide (a selective CYP3A4 inactivator) in order to calculate the contribution of CYP3A5 to metabolism. Drugs with the highest contribution of CYP3A5 included atazanavir, vincristine, midazolam, vardenafil, otenabant, verapamil, and tacrolimus while seventeen of the thirty-two tested showed negligible CYP3A5 contribution. For specific reactions in HLM from *1/*1 donors, CYP3A5 contributes 55 and 44% to midazolam 1'- and 4-hydroxylation, 16% to testosterone 6β-hydroxylation, 56 and 19% to alprazolam 1'- and 4-hydroxylation, 10% to tamoxifen N-demethylation, and 58% to atazanavir p-hydroxylation. A comparison of the in vitro observations to clinical pharmacokinetic data showed only a weak relationship between estimated contribution by CYP3A5 and impact of CYP3A5 genotype on oral clearance, due in large part to the scatter in clinical data and low numbers of study subjects used in CYP3A5 pharmacogenetics studies. These data should be useful in guiding which drugs should be evaluated for differences in pharmacokinetics and metabolism between subjects expressing CYP3A5 and those who do not express this enzyme.
    Drug metabolism and disposition: the biological fate of chemicals 04/2014; 42(7). DOI:10.1124/dmd.114.057000 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Poisoning can occur with chronic accumulation of a drug due to reduced metabolic capacity; conversely, under-treatment may occur due to an increased metabolic rate. Over half of all drugs are metabolized by the cytochrome P450 3A complex (CYP3A). The activity of CYP3A can be assessed by the urinary ratio of 6β-hydroxycortisol to cortisol. The aim of this study was to determine the usefulness of this ratio as a postmortem marker for determining whether altered CYP3A enzyme activity occurred prior to death. In a series of 244 postmortem cases, this ratio ranged from 0.014 to 78.6 (median 3.50). The median was significantly higher (5.14) in a subgroup of 28 cases that exhibited the presence of CYP3A-inducing drugs. In cirrhosis, the median ratio was 1.69. This pointed to a reduced metabolic capacity of CYP3A. Thus, the ratio may constitute a rough indicator of the CYP3A metabolic capacity, which could be of value in special cases.
    Journal of Forensic Sciences 02/2014; 59(4). DOI:10.1111/1556-4029.12418 · 1.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During the process of drug discovery the pharmaceutical industry is faced with numerous challenges. One challenge is the successful prediction of the major routes of human clearance of new medications. For compounds cleared by metabolism, accurate predictions help provide an early risk assessment of their potential to exhibit significant inter-patient differences in pharmacokinetics via routes of metabolism catalyzed by functionally polymorphic enzymes and/or clinically significant metabolic drug-drug interactions (DDIs). This review details the most recent and emerging in vitro strategies utilized by drug metabolism and pharmacokinetic (DMPK) scientists to better determine rates and routes of metabolic clearance and how to translate these parameters to estimate the proportion these routes contribute to overall clearance, commonly referred to as fraction metabolized (fm). The enzymes covered in this review include cytochrome P450s together with other enzymatic pathways whose involvement in metabolic clearance have become increasingly important as efforts to mitigate cytochrome P450 clearance are successful. Advances in the prediction of the fraction metabolized include newly developed methods to differentiate CYP3A4 from the polymorphic enzyme CYP3A5, scaling tools for UDP-glucuronosyltranferase (UGT) and estimating fraction metabolized for substrates of aldehyde oxidase.
    Drug metabolism and disposition: the biological fate of chemicals 10/2014; DOI:10.1124/dmd.114.058750 · 3.74 Impact Factor

Full-text

Download
15 Downloads
Available from
Jul 8, 2014