Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein-Mediated Drug-Drug Interactions in Healthy Volunteers.
Clin Pharmacol Ther
; 109(2): 507-516, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-32866300
ABSTRACT
Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1 -methylnicotinamide (1-NMN)), N1 -methyladenosine (m1 A) was included as novel biomarkers. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well-correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.
Texto completo:
1
Temas:
ECOS
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Aspectos_gerais
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Equidade_desigualdade
Bases de dados:
MEDLINE
Assunto principal:
Biomarcadores
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Proteínas de Transporte de Cátions Orgânicos
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Interações Medicamentosas
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Etiology_studies
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Risk_factors_studies
Limite:
Adult
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Humans
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Male
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão