6-Deoxyacyclovir: a xanthine oxidase-activated prodrug of acyclovir

Abstract

Acyclovir [9-[(2-hydroxyethoxy)methyl]guanine] is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6- deoxyacyclovir [2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine], was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6- deoxyacyclovir [2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine] and then to 8- hydroxyacyclovir [2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methyl]-9H-purine]. 6- Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6- deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase. In rats dosed orally with 6- deoxyacyclovir , absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6- deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.