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.
Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
T C
TC
Burnette
G W
GW
Koszalka
T A
TA
Krenitsky
P
P
De Miranda
D000284:Administration, Oral; D000818:Animals; D001087:Arabinonucleosides / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008862:Microsomes, Liver; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity
D001087:Arabinonucleosides; C008099:hypoxanthine arabinoside; C069956:6-methoxypurine arabinoside