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Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man

  • Pharmacodynamics and Disposition
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Abstract

Objective

To investigate the usefulness of the 3-hydroxylation of quinine as a biomarker reaction for the activity of CYP3A4 in man and to study the interindividual variation in the metabolic ratio (MR), i.e. quinine/3-hydroxyquinine.

Methods

Data from a previous study (A) was used for determination of the MR of quinine in plasma and urine at different time points. In study B, 24 healthy Swedish subjects received 250 mg quinine hydrochloride first alone and later together with four other CYP probe drugs [losartan (CYP2C9), omeprazole (CYP2C19), debrisoquine (CYP2D6) and caffeine (CYP1A2)] administered on the same day. Plasma and urine samples were collected before quinine intake and 16 h thereafter and analysed for quinine and 3-hydroxyquinine using high-performance liquid chromatography. Plasma and/or urine were collected for the other probes at different time points. MRs of all the probes were determined and correlations to quinine MR were studied.

Results

In study A, the MR in plasma was stable over 96 h. The ratio increased from 5.8 to 12.2 (P=0.006) during co-administration with ketoconazole, whereas no significant difference (P=0.76) was observed during co-administration with fluvoxamine (from 5.8 to 6.0). In study B, there was no significant difference (P=0.36) between the mean MRs when quinine was given alone (4.7) or together with the four other drugs (4.5). There was a significant correlation between the MR of quinine and omeprazole sulphone formation (r=0.52, P<0.01), but not to the MRs of the other probes. There was a fivefold interindividual variability in the MR.

Conclusions

The MR of quinine in plasma or urine may serve as a stable measure of the activity of CYP3A4 in man. These results together with in vitro data show that quinine is also a specific CYP3A4 probe.

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Acknowledgements

The study was financially supported by the Swedish Agency for Research Cooperation with Developing Countries Grant Bil Tz 16/98 75007059, SWE 1997–221, 1998–394, 1999–260, 2000–175, the Swedish Medical Research Council grant no. 3902, Karolinska Institutet, the National Institutes of Health, USA (1R01 GM60548–02), and Pfizer Ltd, Sandwich, UK. Our thanks are extended to the research nurses Anneli Wahlberg and Katarina Andersson for their excellent help in the study.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology, Karolinska Institutet and Hospital Pharmacy, C1-68 Huddinge University Hospital, 141 86 , Stockholm, Sweden

    Rajaa A. Mirghani, Örjan Ericsson, Gunnel Tybring, Lars L. Gustafsson & Leif Bertilsson

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  1. Rajaa A. Mirghani
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  2. Örjan Ericsson
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  3. Gunnel Tybring
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Correspondence to Rajaa A. Mirghani.

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Mirghani, R.A., Ericsson, Ö., Tybring, G. et al. Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. Eur J Clin Pharmacol 59, 23–28 (2003). https://doi.org/10.1007/s00228-003-0575-5

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