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A cytochrome P450 phenoty** cocktail causing unexpected adverse reactions in female volunteers

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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 02 March 2014

Abstract

Background

A four-drug cytochrome P450 (CYP) phenoty** cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype.

Methods

The cocktail consisted of the single CYP phenoty** probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post-administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes.

Results

In a pilot study in 12 healthy male volunteers the CYP genotype–phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 25 subjects (17 males, 7 females).

Conclusion

Attention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine.

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Acknowledgments

This study was supported by grants from The Danish Research Council for Health and Disease (09–065539) and the Lundbeck Foundation (R32-A3119).

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Authors and Affiliations

  1. Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winslowsvej 19, 5000, Odense, Denmark

    Rasmus Steen Pedersen, Per Damkier, Mette Marie Hougaard Christensen & Kim Brosen

  2. Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark

    Per Damkier

Authors
  1. Rasmus Steen Pedersen
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  2. Per Damkier
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  3. Mette Marie Hougaard Christensen
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  4. Kim Brosen
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Correspondence to Rasmus Steen Pedersen.

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Pedersen, R.S., Damkier, P., Christensen, M.M.H. et al. A cytochrome P450 phenoty** cocktail causing unexpected adverse reactions in female volunteers. Eur J Clin Pharmacol 69, 1997–1999 (2013). https://doi.org/10.1007/s00228-013-1561-1

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  • DOI: https://doi.org/10.1007/s00228-013-1561-1

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