Carboxylesterase 1 genetic variability, expression and potential for drug-drug interations

Sánchez Pascua, Teresa
Carboxylesterase 1 genetic variability, expression and potential for drug-drug interations. PhD thesis, University of Liverpool.

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Carboxylesterase 1 (CES1) is the main human liver esterase and is involved in the metabolism and disposition of numerous endogenous and pharmacological compounds. Some of the substrates of this enzyme are widely prescribed agents such as clopidogrel (Plavix®), methylphenidate (Ritalin®) and oseltamivir (Tamiflu®). However, there is much uncertainty regarding the genetic variability within CES1, and its regulation and involvement in drug-drug interactions (DDI). Polypharmacy is frequent in elderly, HIV and tuberculosis infected populations, and the risk of harmful DDIs is high, especially when these populations overlap. The role played by CES1 on the treatment of all these three pathologies and vice versa needs to be better characterized. In this thesis the role of CES1 genetic variability and its potential role in DDIs are explored both in isolation and in conjunction with other genetic, demographic, physio-pathological and iatrogenic factors. The impact of CES1 genetic variability was assessed on the anti-platelet effect of clopidogrel as well as on isoniazid pharmacokinetics in acute coronary syndrome (ACS) and HIV/Tuberculosis co-infected populations respectively. DDIs mediated by CES1 were explored in a HIV positive cohort treated with clopidogrel and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Also, in vitro experiments with primary hepatocytes were used to investigate CES1 intracellular expression in the presence of prototypical PXR inducers used in tuberculosis treatment. The results of this thesis show that the CES1 rs2244613 SNP does affect clopidogrel anti-aggregant activity and may contribute to treatment non-response. Another CES1 variant, rs3815583, was found to be associated with changes in isoniazid pharmacokinetics. The studies did not indicate that NNRTI coadministration with clopidogrel would impair the anti-platelet activity since no relevant changes in exposure of the antiplatelet agent were identified. In the same way, the results do not anticipate DDIs between CES1 substrates and rifamycins, since no induction of expression was identified after incubating primary human hepatocytes in vitro with rifampicin, rifabutin and rifapentine. In conclusion, the results shown in this thesis support the idea that CES1 genetic variability may play a bigger role than previously suspected in treatment response but may not be a mediator of clinically relevant DDIs.

Item Type: Thesis (PhD)
Additional Information: Date: 2014-09-30 (completed)
Subjects: ?? QH426 ??
?? RM ??
Depositing User: Symplectic Admin
Date Deposited: 05 Aug 2015 09:33
Last Modified: 17 Dec 2022 01:34
DOI: 10.17638/02006752