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Organic cation transporters OCT1 and OCT2 determine the accumulation of lamivudine in CD4 cells of HIV-infected patients

  • Clinical and Epidemiological Study
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Abstract

Purpose

Identifying factors that determine concentrations of antiretroviral drugs in CD4 cells are important for improving therapeutic efficacy. Experimental models indicate that the nucleoside reverse transcriptase inhibitor lamivudine is transported by the organic cation transporters 1 and 2 (OCT1 and OCT2, respectively). Here, we tested whether OCT1 and OCT2 contribute to the uptake of lamivudine into native CD4 cells of human immunodeficiency virus (HIV)-infected individuals.

Methods

CD4 cells obtained by non-activated cell sorting from 35 individuals with HIV-1 infection were incubated with lamivudine (10 μM, 30 min), and intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate were determined by liquid chromatography tandem mass spectrometry. The expression of OCT1 and OCT2 mRNA was measured by quantitative real-time polymerase chain reaction (PCR). A model of OCT2-transfected CD4 cells was established for mechanistic investigations.

Results

Intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate showed strong linear correlations with each other and with the CD4 mRNA expression of OCT1 and OCT2 (r > 0.80). Coincubation with protease inhibitors (ritonavir, nelfinavir) that inhibit OCT1 and OCT2 yielded decreased intracellular concentrations of lamivudine and lamivudine triphosphate. Incubation of CD4 cells from healthy donors transfected with an OCT2 expression vector yielded increased concentrations of lamivudine and lamivudine triphosphate.

Conclusion

Our studies indicate a role of OCT1 and OCT2 for the cellular accumulation of lamivudine in HIV-infected individuals.

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Acknowledgments

We thank Kathi Krüsemann for the excellent technical assistance. We thank Tim Kümmerle, Susann Koch, and Andrea Birtel for their help with the recruitment of patients. This work was supported by the German Federal Ministry of Research and Education (BMBF) (grant numbers 01KI0771 to N.J., C.L., G.F., and P.H.).

Conflict of interest

Nothing to declare.

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Authors and Affiliations

  1. First Department of Internal Medicine, Medical Hospital of the University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    N. Jung, C. Lehmann, A. Rubbert, G. Fätkenheuer & P. Hartmann

  2. Department of Pharmacology, Medical Hospital of the University of Cologne, Gleueler Str. 24, 50931, Cologne, Germany

    E. Schömig & D. Taubert

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  1. N. Jung
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  2. C. Lehmann
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  3. A. Rubbert
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  5. G. Fätkenheuer
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  6. P. Hartmann
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  7. D. Taubert
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Correspondence to N. Jung.

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Jung, N., Lehmann, C., Rubbert, A. et al. Organic cation transporters OCT1 and OCT2 determine the accumulation of lamivudine in CD4 cells of HIV-infected patients. Infection 41, 379–385 (2013). https://doi.org/10.1007/s15010-012-0308-8

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  • DOI: https://doi.org/10.1007/s15010-012-0308-8

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