title: Pharmacokinetics of the antiviral agent beta-L-3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine in rhesus monkeys.
abstract: beta-L-3'-Fluoro-2',3'-didehydro-2',3'-dideoxycytidine (L-3'-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of L-3'-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of L-3'-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (P = 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: Ghazia
authors.initials: G
authors.lastname: Asif
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gumina
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 / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001639:Bicarbonates / Q000494:pharmacology; D001682:Biological Availability; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008253:Macaca mulatta; D012015:Reference Standards; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C498057:3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine; D000998:Antiviral Agents; D001639:Bicarbonates; D002021:Buffers; D016047:Zalcitabine