title: Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons.
abstract: OBJECTIVE
  To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy.
  
  
  METHODS
  Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir.
  
  
  METHODS
  Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses.
  
  
  RESULTS
  Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate.
  
  
  CONCLUSIONS
  These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota Academic Health Sciences Center, Minneapolis 55455, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: S P
authors.initials: SP
authors.lastname: Kawle
authors.forename: T N
authors.initials: TN
authors.lastname: Kakuda
authors.forename: P L
authors.initials: PL
authors.lastname: Anderson
authors.forename: D
authors.initials: D
authors.lastname: Weller
authors.forename: L R
authors.initials: LR
authors.lastname: Bushman
authors.forename: R C
authors.initials: RC
authors.lastname: Brundage
authors.forename: R P
authors.initials: RP
authors.lastname: Remmel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006678:HIV; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000032:analysis; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013942:Thymine Nucleotides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015215:Zidovudine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C417268:lamivudine triphosphate; D019259:Lamivudine; D015215:Zidovudine; D003570:Cytidine Triphosphate; C052873:zidovudine triphosphate