Abstract
The Karolinska cocktail, comprising caffeine, losartan, omeprazole, and quinine, was given before and after administration of rifampicin (20, 100, or 500 mg daily) to measure induction of cytochrome P450 (P450) enzymes. Rifampicin was given for 14 days to eight healthy subjects (all of whom possessed at least one wild-type CYP2C9 and one wild-type CYP2C19 gene) in each dose group. 4beta-hydroxycholesterol was assessed as an endogenous marker of CYP3A4 induction. A fourfold induction of CYP3A4 was seen at the highest dose by both quinine:3'-hydroxyquinine and 4beta-hydroxycholesterol measurements (P < 0.001). CYP3A4 was also induced at the two lower doses of rifampicin when measured by these two markers (P < 0.01 or P < 0.001). CYP1A2, CYP2C9, and CYP2C19 were induced after 500 mg rifampicin daily (1.2-fold, P < 0.05; 1.4-fold, P < 0.05; and 4.2-fold, P < 0.01, respectively). In conclusion, we have shown that the Karolinska cocktail and 4beta-hydroxycholesterol can be used for an initial screening of the induction properties of a drug candidate.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Anti-Ulcer Agents / administration & dosage
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Anti-Ulcer Agents / blood
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Anti-Ulcer Agents / pharmacology
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Antibiotics, Antitubercular / pharmacology*
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / urine
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Antimalarials / administration & dosage
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Antimalarials / metabolism
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Antimalarials / pharmacology
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Caffeine / administration & dosage
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Caffeine / blood
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Caffeine / pharmacology
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Central Nervous System Stimulants / administration & dosage
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Central Nervous System Stimulants / blood
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Central Nervous System Stimulants / pharmacology
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Cytochrome P-450 Enzyme System / biosynthesis*
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Cytochrome P-450 Enzyme System / physiology
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Drug Combinations
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Enzyme Induction / drug effects
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Female
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Humans
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Hydroxycholesterols / blood*
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Losartan / administration & dosage
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Losartan / pharmacology
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Losartan / urine
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Male
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Middle Aged
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Omeprazole / administration & dosage
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Omeprazole / blood
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Omeprazole / pharmacology
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Quinine / administration & dosage
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Quinine / metabolism
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Quinine / pharmacology
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Rifampin / pharmacology*
Substances
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Anti-Ulcer Agents
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Antibiotics, Antitubercular
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Antihypertensive Agents
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Antimalarials
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Central Nervous System Stimulants
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Drug Combinations
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Hydroxycholesterols
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cholest-5-ene-3,4-diol
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Caffeine
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Cytochrome P-450 Enzyme System
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Quinine
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Losartan
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Omeprazole
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Rifampin