Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys.

The metabolism and pharmacokinetics of 6-methoxypurine arabinoside (ara-M), a potent and selective inhibitor of varicella-zoster virus, were investigated in rats and monkeys. In Long Evans rats, orally administered [8-14C]ara-M (10 mg/kg) was well absorbed but extensively metabolized to hypoxanthine arabinoside (ara-H), hypoxanthine, xanthine, uric acid, and allantoin. Only 4% of an oral dose was recovered in the urine as unchanged drug, compared with 40% of an intravenous dose, indicating significant presystemic metabolism. Pretreatment of rats with 1-aminobenzotriazole, an inhibitor of cytochrome P-450, did not alter this metabolism. Pretreatment with deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride, inhibitors of adenosine deaminase, resulted in a marked decrease in ara-M metabolism, indicating that adenosine deaminase plays a major role in the biotransformation of ara-M. In cynomolgus monkeys, [8-14C]ara-M (10 mg/kg) administered intravenously or orally was extensively metabolized to ara-H. Several minor urinary metabolites were detected in both rats and monkeys. However, adenine arabinoside was not found in urine or plasma from either rats or monkeys after administration of ara-M, except for a very low level detected in the urine of rats pretreated with deoxycoformycin. The elimination half-lives of intravenously administered ara-M in rats and monkeys were 29 and 45 min, respectively. The corresponding half-lives of the primary metabolite, ara-H, were 44 min and 2.3 h. Plasma profiles of orally administered ara-M in both rats and monkeys demonstrated the poor oral bioavailability of this arabinoside. The results of these studies indicate that ara-M is not well suited for oral administration because of extensive presystemic metabolism.

Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients.

Over 25 episodes of severe chronic and recurrent mucocutaneous herpes simplex virus infections in five immunodeficient patients were successfully treated with intravenous or oral acyclovir treatment. Acyclovir was shown to inhibit viral shedding rapidly, to be well tolerated, and to permit the complete healing of lesions. As expected, a course of acyclovir did not prevent later recurrences of the herpes virus infections. However, symptomatic recurrences were successfully suppressed during long (up to 65-day) courses of oral acyclovir.