title: The bioavailability and disposition of 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil (882C87), a potent, new anti-varicella zoster virus agent.
abstract: 1. The bioavailability and disposition of 882C87, an anti-varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. 2. The mean bioavailability of a 200 mg tablet was 21.1% in the young (range 13.3-33.0%, n = 10) and 24.6% in the elderly (range 14.4-38.4%, n = 8), which is sufficient to achieve plasma concentrations well above the IC50 for anti-VZV activity. 3. Plasma concentrations of 882C87 after 50 mg i.v. were higher in the elderly than in the young, associated with a significantly longer half-life (13.7 vs 11.8 h) and decreased renal clearance (0.11 vs 0.14 ml min-1 kg-1) and total clearance (0.15 vs 0.17 ml min-1 kg-1). 4. After intravenous administration, the main route of elimination of 882C87 was renal with 81.6% recovered unchanged in urine in the young and 71.2% in the elderly. The pyrimidine base, 5-propynyluracil (5-PU) was unquantifiable in plasma and only present in trace amounts in urine. 5. After oral administration to four healthy volunteers, only 17% of a dose of [14C]-882C87 was recovered unchanged in urine and 58% as 5-PU, with total recovery in urine accounting for 86% of the dose. There was a lag of 4-12 h before the appearance of 5-PU in plasma, peak concentrations were one-third to a half those of 882C87. The data suggest that 5-PU is formed from unabsorbed 882C87 in the gut lumen and then absorbed and excreted in urine. 6. 882C87 is a potential once daily treatment for shingles.
authors.affiliation: Department of Clinical Pharmacology, Wellcome Foundation Ltd., Beckenham, Kent.
authors.forename: R W
authors.initials: RW
authors.lastname: Peck
authors.forename: R
authors.initials: R
authors.lastname: Wootton
authors.forename: D R
authors.initials: DR
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Jackson
authors.forename: J
authors.initials: J
authors.lastname: Posner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001682:Biological Availability; D005260:Female; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008297:Male
chemical_list: D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C067854:5-propynylarabinofuranosyluracil