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

Abstract

Acyclovir {9-[(2-hydroxyethoxy)methyllguanine} 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)methylj-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.Acyclovir {9-[(2-hydroxyethoxy)methylJguanine; Zovirax} is a clinically useful antiherpetic agent (1, 2). Intravenous (3, 4), oral (5), or topical (6, 7) administration provides-effective therapy. Only 15-20% of the dose is typically absorbed in humans after oral administration (8). This degree of absorption is adequate for efficacy against herpes simplex infections (5). However, greater absorption might be important in therapy against less sensitive viruses such as varicella-zoster virus (9). The clinical experience to date clearly indicates that although acyclovir represents a major therapeutic advance in the treatment of herpetic infections, a means of enhancing gastrointestinal absorption would significantly extend its usefulness.Considerable effort has been expended in attempts to find a prodrug that is well absorbed after oral administration and then converted to acyclovir. Esterification of the hydroxyl group of the (2-hydroxyethoxy)methyl moiety of acyclovir has been an approach taken by two separate laboratories (10,11). Unfortunately, those esters that have been tested showed no significant improvement in absorption after oral dosing (unpublished results).The 6-deoxy-6-amino congener of acyclovir {2,6-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purine} (...

Influence of a niosomal formulation on the oral bioavailability of acyclovir in rabbits

“…Trials that have been made to improve the oral bioavailability of acyclovir concerned mainly with chemical modification of the drug. 9,10 Luengo et al 11 studied the pharmacokinetics of different preparations of acyclovir with β-cyclodextrin and found that β-cyclodextrin showed no significant effect on the oral drug bioavailability. This finding is because the effect of cyclodextrin was mainly on the solubility of the lipophilic drug not the permeability of the hydrophilic drug.…”

Identification of an N‐hydroxyguanidine reducing activity of xanthine oxidase

“…Current interest in XO comes from its ability to activate prodrugs [33] and its proposed role in postischemic tissue damage due to oxygen-derived radicals [34Ϫ36]. Guanoxabenz has been used as a centrally active antihypertensive whose action is presumed to be mediated by activation of A 2 -adrenoceptors [37].…”

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…As it was mentioned before, molybdenum hydroxylases can catalyze the oxidation of a wide range of aldehydes and N-heterocyclic compounds (Beedham, 2010;Rashidi & Nazemiyeh, 2010). Purines are among those N-heterocyclic compounds that may be oxidized by AO and XO either as a prodrug converted to its active form (Krenitsky et al, 1984;Rashidi et al, 1997) or during their catabolic pathways (Rashidi et al, 2007). However, the manner of oxidation by these two enzymes could be different from one compound to another.…”

“…7); however, both in vivo and in vitro studies have also shown that penciclovir is the major metabolite of famciclovir metabolism (Pue & Benet, 1993;Pue et al, 1994;Rashidi et al, 1997). Although the oxidative step was initially attributed to XO, on the basis of studies performed with 6-deoxyaciclovir and a structural similarity between 6-deoxypenciclovir and guanine which is a substrate of XO (Harrell et al, 1993;Krenitsky et al, 1984;Vere Hodge et al, 1989), later studies demonstrated that AO is the major enzyme in oxidative conversion of famciclovir to penciclovir (Clarke et al, 1995;Rashidi et al, 1997).…”

“…Development of a prodrug of aciclovir with a better absorption from the gastrointestinal tract and then conversion in vivo to aciclovir has been one of the most common strategies used to achieve this goal Hay CM, Reichman 2008;Krenitsky et al, 1984).…”