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Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men. 2008

Julie B Dumond, and Y Sunila Reddy, and Luigi Troiani, and Jose F Rodriguez, and Arlene S Bridges, and Susan A Fiscus, and Geoffrey J Yuen, and Myron S Cohen, and Angela D M Kashuba
University of North Carolina at Chapel Hill, 3318 Kerr Hall, CB 7360, Chapel Hill, NC 27599-7360, USA.

OBJECTIVE To quantitate extracellular and intracellular zidovudine (ZDV) and lamivudine (3TC) concentrations in blood and semen of HIV-1-infected men. METHODS : Nonblind, single-center, open-label pharmacokinetic (PK) study in 14 subjects receiving ZDV plus 3TC. METHODS Paired blood and semen samples were obtained during 1 intensive visit and 3 single time point visits over 2 weeks. Extracellular ZDV and 3TC concentrations were measured in blood plasma (BP) and seminal plasma (SP), and intracellular ZDV and 3TC triphosphate (TP) concentrations were measured in isolated mononuclear cells using validated methods. HIV-1 RNA was measured in blood and semen. PK parameters were estimated using noncompartmental analysis. RESULTS Median (interquartile range [IQR]) SP/BP area under the time-concentration curve over the 12-hour dosing interval (AUC0-12h) ratios for ZDV and 3TC were 2.28 (1.48 to 2.97) and 6.67 (4.10 to 9.14), respectively, whereas individual SP/BP concentration ratios ranged from 1.9 to 91.4. Intracellular median (IQR) SP/BP AUC0-12h ratios for ZDV-TP and 3TC-TP were 0.36 (0.30 to 0.37) and 1.0 (0.62 to 1.30), respectively, whereas individual SP/BP concentration ratios ranged from 0.11 to 2.9. HIV-1 RNA was undetectable in both compartments. CONCLUSIONS ZDV and 3TC SP exposures are 2- to 6-fold greater than BP exposures. Seminal ZDV-TP exposures are approximately 40% of those found in peripheral blood mononuclear cells (PBMCs), whereas 3TC-TP exposures are similar to PBMC exposures. PK variability makes individual SP/BP ratios a suboptimal surrogate for genital tract exposure.

UI MeSH Term Description Entries
D007424 Intracellular Fluid The fluid inside CELLS. Fluid, Intracellular,Fluids, Intracellular,Intracellular Fluids
D008297 Male Males
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000163 Acquired Immunodeficiency Syndrome An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive T-lymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. AIDS,Immunodeficiency Syndrome, Acquired,Immunologic Deficiency Syndrome, Acquired,Acquired Immune Deficiency Syndrome,Acquired Immuno-Deficiency Syndrome,Acquired Immuno Deficiency Syndrome,Acquired Immuno-Deficiency Syndromes,Acquired Immunodeficiency Syndromes,Immuno-Deficiency Syndrome, Acquired,Immuno-Deficiency Syndromes, Acquired,Immunodeficiency Syndromes, Acquired,Syndrome, Acquired Immuno-Deficiency,Syndrome, Acquired Immunodeficiency,Syndromes, Acquired Immuno-Deficiency,Syndromes, Acquired Immunodeficiency
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D012367 RNA, Viral Ribonucleic acid that makes up the genetic material of viruses. Viral RNA
D012661 Semen The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains SPERMATOZOA and their nutrient plasma. Seminal Plasma,Plasma, Seminal
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D045604 Extracellular Fluid The fluid of the body that is outside of CELLS. It is the external environment for the cells. Interstitial Fluid,Intercellular Fluid,Extracellular Fluids,Fluid, Extracellular,Fluid, Intercellular,Fluid, Interstitial,Fluids, Extracellular,Fluids, Intercellular,Fluids, Interstitial,Intercellular Fluids,Interstitial Fluids

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