1. ¹Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden
2. ²Department of Development DMPK and Bioanalysis, AstraZeneca R&D Mölndal, Mölndal, Sweden
3. ³Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden
4. ⁴Department of Clinical Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden
5. ⁵Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Correspondence: L Bertilsson, (Leif.Bertilsson@ki.se)

Received 25 April 2008; Accepted 17 May 2008; Published online 23 July 2008.

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. 4-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 4-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 4-hydroxycholesterol can be used for an initial screening of the induction properties of a drug candidate.