The acyclic
guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]
guanine, (+/-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus
infections in vitro. This report is concerned with the pharmacokinetic evaluation of the
drug in rats and monkeys and its
antiviral activity in African green monkeys infected with simian
varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+/-)2HM-HBG. Elimination half-lives in plasma following
intravenous administration to monkeys (100 mumol/kg of
body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 +/- 0.4 ml/min per kg (mean +/- standard error). After
oral administration, levels in plasma were low, with a maximum concentration of the
drug of only 3.1 +/- 0.8 microM, a time to reach maximum concentration of
drug of 2.7 +/- 0.4 h, and an oral bioavailability of 10.6 +/- 1.4%. Because of the low oral bioavailability, SVV-infected monkeys were treated intramuscularly with (+/-)2HM-HBG. (+/-)2HM-HBG at a dosage of 10 mg/kg of
body weight per day allowed moderate
viremia, whereas a dosage of 30 mg/kg of
body weight per day strongly suppressed
viremia with minimal numbers of virus plaques from blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (+/-)2HM-HBG is an effective inhibitor of SVV replication in vivo, despite the fact that leves of (+/-)2HM-HBG in plasma were low at extended periods of time and below the concentration of
drug giving 50% inhibition of plaque formation obtained in vitro.