N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction.
Eur J Clin Pharmacol
; 71(1): 85-94, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25552403
ABSTRACT
PURPOSE:
N(1)-methylnicotinamide (NMN) was proposed as an in vivo probe for drug interactions involving renal cation transporters, which, for example, transport the oral antidiabetic drug metformin, based on a study with the inhibitor pyrimethamine. The role of NMN for predicting other interactions with involvement of renal cation transporters (organic cation transporter 2, OCT2; multidrug and toxin extrusion proteins 1 and 2-K, MATE1 and MATE2-K) is unclear.METHODS:
We determined inhibition of metformin or NMN transport by trimethoprim using cell lines expressing OCT2, MATE1, or MATE2-K. Moreover, a randomized, open-label, two-phase crossover study was performed in 12 healthy volunteers. In each phase, 850 mg metformin hydrochloride was administered p.o. in the evening of day 4 and in the morning of day 5. In phase B, 200 mg trimethoprim was administered additionally p.o. twice daily for 5 days. Metformin pharmacokinetics and effects (measured by OGTT) and NMN pharmacokinetics were determined.RESULTS:
Trimethoprim inhibited metformin transport with K i values of 27.2, 6.3, and 28.9 µM and NMN transport with IC50 values of 133.9, 29.1, and 0.61 µM for OCT2, MATE1, and MATE2-K, respectively. In the clinical study, trimethoprim increased metformin area under the plasma concentration-time curve (AUC) by 29.5 % and decreased metformin and NMN renal clearances by 26.4 and 19.9 %, respectively (p ≤ 0.01). Moreover, decreases of NMN and metformin renal clearances due to trimethoprim correlated significantly (r S=0.727, p=0.010).CONCLUSIONS:
These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trimetoprima
/
Niacinamida
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Proteínas de Transporte de Cátions Orgânicos
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Hipoglicemiantes
/
Rim
/
Metformina
Tipo de estudo:
Clinical_trials
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Eur J Clin Pharmacol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Alemanha