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

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...

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Bibliographic Details
Published in:Infection 2013-04, Vol.41 (2), p.379-385
Main Authors: Jung, N., Lehmann, C., Rubbert, A., Schömig, E., Fätkenheuer, G., Hartmann, P., Taubert, D.
Format: Article
Language:English
Subjects:
Adult
Antiretroviral Therapy, Highly Active
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - metabolism
Clinical and Epidemiological Study
Cytidine Triphosphate - administration & dosage
Cytidine Triphosphate - analogs & derivatives
Cytidine Triphosphate - pharmacokinetics
Dideoxynucleotides - administration & dosage
Dideoxynucleotides - pharmacokinetics
Family Medicine
Female
General Practice
HIV Infections - drug therapy
HIV Protease Inhibitors - administration & dosage
HIV Protease Inhibitors - pharmacokinetics
HIV-1 - drug effects
Human immunodeficiency virus 1
Humans
Infectious Diseases
Internal Medicine
Lamivudine - administration & dosage
Lamivudine - analogs & derivatives
Lamivudine - pharmacokinetics
Male
Medicine
Medicine & Public Health
Middle Aged
Nelfinavir - pharmacology
Organic Cation Transport Proteins - genetics
Organic Cation Transport Proteins - metabolism
Organic Cation Transporter 1 - genetics
Organic Cation Transporter 1 - metabolism
Organic Cation Transporter 2
Phosphorylation
Real-Time Polymerase Chain Reaction
Ritonavir - pharmacology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tandem Mass Spectrometry
Transfection
Young Adult
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Summary: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.
ISSN:0300-8126
1439-0973
DOI:10.1007/s15010-012-0308-8