Antiviral drugs with extra‐cellular sites of action

As the number of licensed antiviral drugs has increased (29 are now available in the US and/or Europe), we have become accustomed to learning their intracellular pathways of metabolism to allow inhibition of intracellular sites of viral replication, as well as their potential toxicity. The pharmacokinetics (PK) of drug activity may be straightforward for compounds such as protease inhibitors or non-nucleoside reverse transcriptase inhibitors, whose active molecules are present in the oral formulation taken by the patient. However, an extra order of magnitude of complexity is found in nucleoside analogues which require intracellular anabolism to create their active form. Thus, zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir are phosphorylated by cellular kinases to their triphosphates, which act as competitive inhibitors of HIV-encoded reverse transcriptase [1]. Furthermore, compounds such as acyclovir, ganciclovir and penciclovir are poor substrates for cellular thymidine kinase but are selectively activated to the monophosphate in herpesvirus-infected cells expressing the thymidine kinase encoded by HSV or VZV or the UL97 gene of CMV, thereafter being converted to the triphosphate by cellular enzymes [2]. This desirable selectivity further complicates their metabolism, as does the availability of prodrug forms (valaciclovir, famciclovir and valganciclovir), which are absorbed and metabolised in the gut wall and/or liver to release the parent compound. An analogous pathway is followed by nucleotide compounds (cidofovir, adefovir, tenofovir) except that, as phosphonates [1], they resemble the monophosphate and so bypass the herpes-induced phosphorylating enzyme phase to be converted by cellular enzymes to their active diphosphate forms (structurally equivalent to a nucleoside triphosphate). The PK of drug metabolism and excretion affect the dosage and timing of drug administration and may alter drug efficacy through PK interactions. For example, zidovudine and stavudine compete in vitro for phosphorylation by cellular enzymes and this interaction explains why this combination of compounds has reduced potency in vivo [3]. The elimination of nucleoside analogues is straightforward, involving glomerular filtration and/or tubular secretion of unmodified compounds to achieve renal excretion. In contrast, the protease inhibitors and non-nucleoside reverse transcriptase inhibitors are metabolised in the liver by the cytochrome P450 system before undergoing renal excretion. Polypharmacy may therefore allow these compounds to both induce the activity of and compete for the P450 system, thereby altering their PK [4]. More importantly, these compounds are, to variable extents, P450 inhibitors able to impair the metabolism of themselves and compounds broken down by the same enzymes. Thus, ritonavir (the most potent P450 inhibitor) greatly increases drug exposure (as measured by the area under the curve of the concentration : time plot) for all of the protease inhibitors; a phenomenon currently being used in a licensed lopinavir/low dose ritonavir preparation and being exploited in clinical trials of low dose ritonavir plus high dose other protease inhibitor [5]. Now comes a series of new antiviral compounds to disturb these neat anabolic pathways. They do not share features such as inhibition of members of the same virus family or route of administration, but have one novel characteristic in common; they act at extracellular sites. The first two compounds are zanamivir and oseltamivir which inhibit the neuraminidase enzymes of influenza A or B, so reducing the ability of nascent virions to escape from the surface of infected cells and travel to infect others. Zanamivir is poorly bioavailable and so is administered via powder inhalation into the lungs [6]. Oseltamivir is also poorly bioavailable and so given orally in prodrug form [7]. Drug disposition must therefore follow the route of cleavage of the ester prodrug in cells of the gut wall, release into extracellular fluid, distribution Reviews in Medical Virology Rev. Med. Virol. 2001; 11: 273–275. DOI: 10.1002/rmv.330