title: Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells.
abstract: The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA jdumond@unc.edu.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Dumond
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA.
authors.forename: Kuo H
authors.initials: KH
authors.lastname: Yang
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA.
authors.forename: Racheal
authors.initials: R
authors.lastname: Kendrick
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA.
authors.forename: Y Sunila
authors.initials: YS
authors.lastname: Reddy
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA School of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: School of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Troiani
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, North Carolina, USA.
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.affiliation: School of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Fiscus
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice, State University of New York, University at Buffalo, Buffalo, New York, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: School of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Cohen
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001692:Biological Transport; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D003198:Computer Simulation; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D054306:Dideoxynucleotides / Q000493:pharmacokinetics* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D015233:Models, Statistical; D012661:Semen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D013942:Thymine Nucleotides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D013942:Thymine Nucleotides; C417268:lamivudine triphosphate; D019259:Lamivudine; D015215:Zidovudine; D003570:Cytidine Triphosphate; C052873:zidovudine triphosphate