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Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study

  • Pharmacogenetics
  • Published:
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Abstract

Objective

To test the hypotheses that (1) CYP2D6 genotype is associated with pharmacokinetics of ophthalmic timolol and (2) variation in genotypes of ADRB1 (β1-adrenoceptor) and GNAS1 (α-subunit of G-protein) modulate heart rate (HR), and systolic (SAP) and diastolic (DAP) arterial pressure responses to timolol.

Methods

Nineteen glaucoma patients and eighteen healthy volunteers were treated with 0.5% aqueous and 0.1% hydrogel formulations of ophthalmic timolol using a randomised cross-over design. The participants conducted head-up tilt and maximum exercise test at four visits. Plasma concentration of timolol was measured twice for glaucoma patients and ten times for healthy volunteers on each visit. Also, the genotypes for CYP2D6, ADRB1 and GNAS1 were determined.

Results

Among healthy volunteers using aqueous timolol, poor metabolisers (PMs, n=2) of CYP2D6 had higher maximum plasma concentrations (Cmax, values 2.63 and 2.94 ng/ml), longer elimination half-lives ( T1/2, 5.49 and 6.75 h), and higher area-under-curve (AUC, 19.54 and 23.25 ng·h/ml) than intermediate [IMs, n=6, mean±SD 1.73±0.59 ng/ml (not significant), 3.30±0.48 h, 11.32±3.72 ng·h/ml], extensive (EMs, n=8, 1.60±0.72 ng/ml, 3.24±1.24 h, 8.52±6.12 ng·h/ml) and ultra-rapid (UMs, n=2, values 1.23 and 1.67 ng/ml, 2.22 and 2.52 h, 6.16 and 6.94 ng·h/ml) metabolisers. The IMs, EMs and UMs did not differ from each other for any of the kinetic variables. Also, the elevation of HR from rest to maximum level tended to differ between PMs and IMs, and between PMs and UMs. The pharmacokinetics and pharmacodynamics between the CYP2D6 groups did not differ with statistical significance when hydrogel timolol was used. Upon head-up tilt, the Ser49 homozygotes (n=26) had higher SAP (P=0.03) and DAP (P<0.01) than the Gly carriers (n=11). The change in DAP from rest to maximum during exercise was lower (P<0.01) in subjects with CC alleles of GNAS1 (n=13) than those with at least one T allele (n=24).

Conclusion

The CYP2D6 poor metabolisers may be more prone to systemic adverse events with aqueous timolol than extensive metabolisers. Since CYP2D6 genotyping is not routine clinical practice, using 0.1% timolol hydrogel instead of 0.5% aqueous preparation will increase patient safety.

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Acknowledgements

Mrs. Pirjo Järventausta and Ms. Nina Peltonen are acknowledged for their skillful technical assistance. The experiments comply with the current Finnish laws.

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Authors and Affiliations

  1. Department of Pharmacological Sciences, Medical School, University of Tampere, 33014, Tampere, Finland

    Tuomo Nieminen

  2. Department of Clinical Physiology, Medical School, University of Tampere, 33014, Tampere, Finland

    Väinö Turjanmaa & Mika Kähönen

  3. Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland

    Mika Kähönen

  4. Department of Ophthalmology, University of Kuopio and Kuopio University Hospital, Kuopio, Finland

    Hannu Uusitalo

  5. Santen Oy, Tampere, Finland

    Jukka Mäenpää

  6. Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Anders Rane & Stefan Lundgren

  7. Santen Oy, Helsinki, Finland

    Auli Ropo

  8. Departments of Clinical Chemistry, Tampere University Hospital and Tampere University Medical School, Tampere, Finland

    Riikka Rontu & Terho Lehtimäki

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  1. Tuomo Nieminen
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Correspondence to Tuomo Nieminen.

Additional information

Financial support has been received from the Medical Research Fund of Tampere University Hospital, Emil Aaltonen Foundation and Santen Oy, Tampere, Finland.

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Nieminen, T., Uusitalo, H., Mäenpää, J. et al. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Eur J Clin Pharmacol 61, 811–819 (2005). https://doi.org/10.1007/s00228-005-0052-4

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  • DOI: https://doi.org/10.1007/s00228-005-0052-4

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