In vitro demonstration of antedrug mechanism of a pharmacokinetic booster to improve CYP3A4 substrates by CYP3A4-mediated metabolism inhibition.
Drug Metab Pharmacokinet
; 56: 101005, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38663182
ABSTRACT
We previously reported novel benzyl-ether derivatives with an imidazole ring and a hydroxyl group (A-01) or carboxyl group (B-01) and esters (2 esters of A-01, and 7 esters of B-01) as pharmacokinetics (PK) boosters. This study demonstrates how these ester compounds embody the concept of a safe pharmacokinetic booster, with potent and transient inhibition of CYP3A4-mediated drug metabolism. As a model CYP3A4 substrate and CYP3A4 enzyme, midazolam (MDZ) and rat liver microsomes were used. A-01 inhibited MDZ metabolism significantly, while B-01 induced only slight inhibition. Although rat liver microsomes hydrolyzed the ester compounds over time, several ester compounds strongly inhibited MDZ metabolism. Due to the significant activity of A-01, A-01 esters affected MDZ metabolism, irrespective of hydrolysis state. Time-dependent inhibition evaluation indicated that the B-01 ester inhibition is not mechanism-based, as hydrolysis eliminated MDZ metabolism inhibition. We report that the B-01 esters significantly inhibit CYP3A4-mediated drug metabolism, and upon hydrolysis this property is eliminated. In conclusion, B-01 ester compounds may be safe PK boosters with antedrug characteristics.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Midazolam
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Microssomos Hepáticos
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Citocromo P-450 CYP3A
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Inibidores do Citocromo P-450 CYP3A
Limite:
Animals
Idioma:
En
Revista:
Drug Metab Pharmacokinet
Assunto da revista:
FARMACOLOGIA
/
METABOLISMO
Ano de publicação:
2024
Tipo de documento:
Article
País de publicação:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM