Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.
Drug Metab Dispos
; 43(6): 819-28, 2015 Jun.
Article
em En
| MEDLINE
| ID: mdl-25795462
ABSTRACT
Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Jejum
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Citocromo P-450 CYP1A2
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Citocromo P-450 CYP2D6
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Citocromo P-450 CYP3A
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Citocromo P-450 CYP2C9
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Citocromo P-450 CYP2C19
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Fígado
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Adult
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Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article