title: Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State.
abstract: The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2-10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106cells, 898-2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106cells, 85-106), seminal cells (22 fmol/106cells, 6-79), and cervical cells (111 fmol/106cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/106cells, 5.2-6.1) and cervical cells (7 pmol/106cells, 2-19) versus rectal (0.8 pmol/106cells, 0.6-1.1) and seminal cells (0.3 pmol/106cells, 0.2-0.5). Genital drug concentrations on days 1-7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+compared with CD4+, CD8+, and CD19+cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Seifert
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Chen
authors.affiliation: 2 Boulder Community Hospital, Beacon Center for Infectious Diseases , Boulder, Colorado.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Meditz
authors.affiliation: 3 Division of Infectious Diseases, School of Medicine, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.affiliation: 4 Denver Public Health , Denver, Colorado.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Gardner
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Predhomme
authors.affiliation: 5 Department of Biostatistics and Informatics, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Clayton
authors.affiliation: 6 School of Medicine, Internal Medicine, Gastroenterology, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Gregory
authors.initials: G
authors.lastname: Austin
authors.affiliation: 7 Division of Allergy and Clinical Immunology, School of Medicine, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Brandon
authors.initials: B
authors.lastname: Klein
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Becky J
authors.initials: BJ
authors.lastname: Kerr
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: L Anthony
authors.initials: LA
authors.lastname: Guida
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Rower
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rower
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: 5 Department of Biostatistics and Informatics, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.affiliation: 1 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus , Aurora, Colorado.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068679:Emtricitabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D005835:Genitalia / Q000737:chemistry*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012007:Rectum / Q000737:chemistry*; D013094:Spermatozoa / Q000737:chemistry; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: HIV pre-exposure prophylaxis; genital compartment; intracellular; nucleoside analog; pharmacokinetics; rectal compartment