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Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study

Derungs, Adrian ; Donzelli, Massimiliano ; Berger, Benjamin ; Noppen, Christoph ; Krähenbühl, Stephan ; Haschke, Manuel

Clinical pharmacokinetics, 2016-01, Vol.55 (1), p.79-91 [Periódico revisado por pares]

Cham: Springer International Publishing

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Título:
Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study
Autor: Derungs, Adrian ; Donzelli, Massimiliano ; Berger, Benjamin ; Noppen, Christoph ; Krähenbühl, Stephan ; Haschke, Manuel
Assuntos: Adult ; Benzoxazines - administration & dosage ; Benzoxazines - pharmacology ; Caffeine - administration & dosage ; Caffeine - pharmacology ; Cross-Over Studies ; Cytochrome P-450 Enzyme Inhibitors - administration & dosage ; Cytochrome P-450 Enzyme Inhibitors - pharmacology ; Genotype ; Humans ; Internal Medicine ; Losartan - administration & dosage ; Losartan - pharmacology ; Male ; Medicine ; Medicine & Public Health ; Metoprolol - administration & dosage ; Metoprolol - pharmacology ; Midazolam - administration & dosage ; Midazolam - pharmacology ; Omeprazole - administration & dosage ; Omeprazole - pharmacology ; Original ; Original Research Article ; Pharmacology/Toxicology ; Pharmacotherapy ; Phenotype ; Young Adult
É parte de: Clinical pharmacokinetics, 2016-01, Vol.55 (1), p.79-91
Notas: ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-News-1
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Descrição: Background and Objective Activity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity. Methods In a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios. Results The Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1′-hydroxymidazolam concentrations after pretreatment of samples with β-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio. Conclusions Inhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies. ClinicalTrials.gov-ID : NCT01386593.
Editor: Cham: Springer International Publishing
Idioma: Inglês

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Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study

Derungs, Adrian ; Donzelli, Massimiliano ; Berger, Benjamin ; Noppen, Christoph ; Krähenbühl, Stephan ; Haschke, Manuel

Cham: Springer International Publishing

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