In:
Basic & Clinical Pharmacology & Toxicology, Wiley, Vol. 122, No. 3 ( 2018-03), p. 341-345
Abstract:
Several single nucleotide variations ( SNV s) affect carboxylesterase 1 ( CES 1) activity, but the effects of genetic variants on CES 1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES 1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES 1 SNV s, rs12443580 and rs8192935, to be strongly and independently associated with a 39% ( p = 4.0 × 10 −13 ) and 31% ( p = 2.5 × 10 −8 ) reduction in CES 1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNV s did not affect CES 1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES 1 c.428G 〉 A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES 1 expression in whole blood but not in the liver. These tissue‐specific effects may result in substrate‐dependent effects of the two SNV s on CES 1‐mediated drug metabolism.
Type of Medium:
Online Resource
ISSN:
1742-7835
,
1742-7843
DOI:
10.1111/bcpt.2018.122.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2151592-X
SSG:
15,3
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