Article ; Online: The relative role of CYP3A4 and CYP3A5 in eplerenone metabolism.
2019 Volume 315, Page(s) 9–13
Abstract: Cytochrome P450 mediated metabolism is the rate-limiting step of elimination for many drugs. CYP3A4 is the most abundant hepatic isoform and CYP3A4/5 metabolize the largest fraction of drugs. Pharmacogenetic studies have not been able to characterize ... ...
| Abstract | Cytochrome P450 mediated metabolism is the rate-limiting step of elimination for many drugs. CYP3A4 is the most abundant hepatic isoform and CYP3A4/5 metabolize the largest fraction of drugs. Pharmacogenetic studies have not been able to characterize population variability in CYP3A4 activity because few variant alleles associated with aberrant enzyme activity have been found. Substrate probes such as midazolam and testosterone have been utilized in-vivo and in-vitro to determine catalytic activity of these enzymes, but they suffer from several limitations. Eplerenone, an aldosterone antagonist, is also metabolized by CYP3A enzymes, and it has the potential to be an excellent substrate probe for CYP3A4/5. Eplerenone's primary metabolite, 6 beta-hydroxyeplerenone is formed preferentially via CYP3A4, however, the relative contribution of CYP3A5 to the 21-hydroxyeplerenone metabolite formation is unknown. Through in-vitro microsomal incubations with recombinant CYP3A4 and CYP3A5 enzymes, we identified their relative contributions to 21-hydroxyeplerenone metabolism. The 21-hydroxy metabolite is formed preferentially via CYP3A5 V |
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| MeSH term(s) | Antihypertensive Agents/metabolism ; Antihypertensive Agents/pharmacology ; Antihypertensive Agents/therapeutic use ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Cytochrome P-450 Enzyme System/pharmacology ; Eplerenone/metabolism ; Eplerenone/pharmacology ; Humans ; Hypertension/drug therapy ; Microsomes/metabolism | |||||
| Chemical Substances | Antihypertensive Agents ; Eplerenone (6995V82D0B) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) | |||||
| Language | English | |||||
| Publishing date | 2019-08-10 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 433788-8 | |||||
| ISSN | 1879-3169 ; 0378-4274 | |||||
| ISSN (online) | 1879-3169 | |||||
| ISSN | 0378-4274 | |||||
| DOI | 10.1016/j.toxlet.2019.08.003 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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