title: Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys.
abstract: Beta-D-dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h(-1); fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Ghazia
authors.initials: G
authors.lastname: Asif
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Obikhod
authors.forename: David
authors.initials: D
authors.lastname: Delinsky
authors.forename: Janarthanan
authors.initials: J
authors.lastname: Narayanasamy
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Harold M
authors.initials: HM
authors.lastname: McClure
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004148:Dioxolanes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D015497:HIV-1; D006207:Half-Life; D007275:Injections, Intravenous; D008253:Macaca mulatta; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D012015:Reference Standards; D015203:Reproducibility of Results; D013941:Thymine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D004148:Dioxolanes; C511146:dioxolane-thymine; D013941:Thymine