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A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression

The Pharmacogenomics Journal volume 2, pages 191–196 (2002)Cite this article

Abstract

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood–brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (χ2 = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01–1.86).

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Acknowledgements

We thank Allison Miller, Isobel Stevens, Robyn Abbott and Dr Sue Luty for contributions to this research. This work was supported by grants from the Health Research Council of New Zealand and Otago University. Rebecca Roberts is a Leslie Averill Fellow of the Canterbury Medical Research Foundation, and Dr Martin Kennedy is a Senior Research Fellow of the Health Research Council of New Zealand.

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Authors and Affiliations

  1. Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand

    R L Roberts & M A Kennedy

  2. Dept of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand

    P R Joyce & R T Mulder

  3. Dept of Medicine, Christchurch School of Medicine, Christchurch, New Zealand

    E J Begg

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  1. R L Roberts
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  2. P R Joyce
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  3. R T Mulder
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  4. E J Begg
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Correspondence to M A Kennedy.

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Roberts, R., Joyce, P., Mulder, R. et al. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J 2, 191–196 (2002). https://doi.org/10.1038/sj.tpj.6500099

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