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. 1995 The British Pharmacological Society