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Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects

  1. Janne T. Backman,
  2. Marjo J. Karjalainen,
  3. Mikko Neuvonen,
  4. Jouko Laitila,
  5. Pertti J. Neuvonen

Article first published online: 21 APR 2006

DOI: 10.1111/j.1365-2125.2006.02653.x

Issue

British Journal of Clinical Pharmacology

British Journal of Clinical Pharmacology

Volume 62, Issue 3, pages 345–357, September 2006

Additional Information

How to Cite

Backman, J. T., Karjalainen, M. J., Neuvonen, M., Laitila, J. and Neuvonen, P. J. (2006), Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. British Journal of Clinical Pharmacology, 62: 345–357. doi: 10.1111/j.1365-2125.2006.02653.x

Author Information

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

*Dr Janne Backman MD, Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290, Helsinki, Finland. Tel: + 358 9 4717 3914 Fax: + 358 9 4717 4039 E-mail: janne.backman@hus.fi

Publication History

  1. Issue published online: 21 APR 2006
  2. Article first published online: 21 APR 2006
  3. Received 11 December 2005Accepted22 February 2006Published OnlineEarly21 April 2006

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Keywords:

  • caffeine;
  • CYP1A2;
  • interaction;
  • rofecoxib;
  • tizanidine

Aims

Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib.

Methods

In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity.

Results

Rofecoxib increased the area under the plasma concentration–time curve (AUC0–∞) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC0−25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01).

Conclusions

Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.

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