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Two separate dose-dependent effects of paroxetine: mydriasis and inhibition of tramadol’s O-demethylation via CYP2D6

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Abstract

Purpose

To investigate paroxetine’s putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol.

Methods

Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/−)-tramadol and (+/−)-O-desmethyltramadol (M1) were determined.

Results

With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45–7.75 mm) before tramadol and 6.22 mm (4.35–7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10–1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60–14.73 (P < 0.001)] and (−)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15–3.77 (P < 0.001)] was also observed.

Conclusions

Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol’s O-demethylation.

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Acknowledgments

We thank the Danish Research Council for Health and Disease; grant number 271-05-0266. We also thank Birgitte Damby Sorensen for analytical expertise.

Competing interests

The head of the research group, K.B., is a member of the Advisory board of the Lundbeck Institute and has previously received funds for members of staff from H. Lundbeck A/S.

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Correspondence to Rasmus Steen Pedersen.

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Nielsen, A.G., Pedersen, R.S., Noehr-Jensen, L. et al. Two separate dose-dependent effects of paroxetine: mydriasis and inhibition of tramadol’s O-demethylation via CYP2D6. Eur J Clin Pharmacol 66, 655–660 (2010). https://doi.org/10.1007/s00228-010-0803-8

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  • DOI: https://doi.org/10.1007/s00228-010-0803-8

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