Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions.
Br J Clin Pharmacol
; 84(9): 1941-1949, 2018 09.
Article
en En
| MEDLINE
| ID: mdl-29665130
ABSTRACT
AIMS:
Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin.METHODS:
In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug.RESULTS:
Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI.CONCLUSIONS:
Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
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Interacciones Farmacológicas
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Desarrollo de Medicamentos
Tipo de estudio:
Clinical_trials
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Diagnostic_studies
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Prognostic_studies
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Screening_studies
Límite:
Adult
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Alemania