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Chapter 17 : Metabolism of Antiviral Nucleosides and Nucleotides

Authors: Adrian S. Ray1, Michael J. M. Hitchcock2
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Affiliations: 1: Preclinical Drug Metabolism, Gilead Sciences, Inc., Foster City, CA 94404; 2: Project and Portfolio Management, Gilead Sciences, Inc., Foster City, CA 94404
Content Type: Monograph
Publication Year: 2009

Category: Viruses and Viral Pathogenesis; Clinical Microbiology

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Abstract:

Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy against human immunodeficiency virus (HIV), herpesviruses (including herpes simplex virus type 1 [HSV-1], HSV-2, varicella-zoster virus, and cytomegalovirus), and the hepatitis B and C viruses (HBV and HCV, respectively). Rather than providing a comprehensive discussion of the metabolism of individual agents, this chapter gives a general overview of enzymes involved in the metabolism of nucleoside and nucleotide analogs. It also highlights a few examples illustrating the unique pharmacology of the molecules. Competing with anabolism, various modes of catabolism and egress can serve to limit the maximal and temporal levels of the active species in target cells. Antiviral nucleoside and nucleotide analogs represent a large structural diversity with analogs mimicking virtually all the natural ribose and 2'-deoxyribose nucleosides and nucleotides. The importance of the 3' hydroxyl in the interaction of nucleosides with nucleoside transporters may differentiate the distribution of 3'-deoxynucleoside analogs and 3'-hydroxyl-containing nucleoside analogs. Anion and cation transporters with more general substrate specificity have also been identified to interact with nucleosides and nucleotides. In addition to anabolic drug interactions, highly catabolized nucleosides can have their levels altered due to interference with their degradation pathways. Drug interactions due to changes in elimination have also been observed to occur between nucleoside and nucleotide analogs and concomitant agents not related to nucleosides. Successful prodrug strategies promise to more effectively target infected tissues while decreasing exposure to sites of toxicity, offering the potential to increase efficacy while decreasing unwanted side effects.

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Metabolism of Antiviral Nucleosides and Nucleotides
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Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
/content/10.1128/9781555815493.ch17.ch17fig01
Figure 1.
Structural diversity of antiviral nucleoside analogs. The structures of the clinically used antiherpes nucleoside brivudin, anti-HCV nucleoside ribavirin, anti-HBV nucleoside entecavir, and the anti-HIV nucleosides zidovudine, stavudine, and emtricitabine (in the absence of the 5-fluoro substitution lamivudine).
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Image of Figure 1.
Figure 1.

Structural diversity of antiviral nucleoside analogs. The structures of the clinically used antiherpes nucleoside brivudin, anti-HCV nucleoside ribavirin, anti-HBV nucleoside entecavir, and the anti-HIV nucleosides zidovudine, stavudine, and emtricitabine (in the absence of the 5-fluoro substitution lamivudine).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 2.
Generic pathways for the permeation, anabolism, and catabolism of nucleoside analogs. Nucleoside analogs can enter the cell through passive diffusion or solute carrier protein-mediated facilitated diffusion (FD), exchange (Ex), or cotrans-port (CT). Once in the cell, nucleoside analogs can be sequentially phosphorylated by nucleoside kinases (NK), NMP kinases (NMPK), and NDP kinases (NDPKs) to their respective NMP, NDP, and NTP analog forms. Nucleoside analogs can be eliminated by catabolic process or effluxed from the cell by ATP binding cassette transporters (ABC).
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Figure 2.

Generic pathways for the permeation, anabolism, and catabolism of nucleoside analogs. Nucleoside analogs can enter the cell through passive diffusion or solute carrier protein-mediated facilitated diffusion (FD), exchange (Ex), or cotrans-port (CT). Once in the cell, nucleoside analogs can be sequentially phosphorylated by nucleoside kinases (NK), NMP kinases (NMPK), and NDP kinases (NDPKs) to their respective NMP, NDP, and NTP analog forms. Nucleoside analogs can be eliminated by catabolic process or effluxed from the cell by ATP binding cassette transporters (ABC).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 3.
Mechanism of renal active tubular secretion of the acyclic nucleotide phosphonate tenofovir that is used in the treatment of HIV and under investigation as a therapy for HBV. Tenofovir is transported from the blood into urine by the combined action of basolateral influx and apical efflux pumps. At the basolateral membrane tenofovir is a better substrate for the organic anion transporter 1 (OAT1) than for OAT3 and is not transported by the organic cation transporters 1 and 2 (OCT1 and OCT2) ( ). At the apical membrane tenofovir is transported by the multidrug-resistance-related protein 4 (MRP4) and is not transported by the breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or MRP2 ( ).
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Image of Figure 3.
Figure 3.

Mechanism of renal active tubular secretion of the acyclic nucleotide phosphonate tenofovir that is used in the treatment of HIV and under investigation as a therapy for HBV. Tenofovir is transported from the blood into urine by the combined action of basolateral influx and apical efflux pumps. At the basolateral membrane tenofovir is a better substrate for the organic anion transporter 1 (OAT1) than for OAT3 and is not transported by the organic cation transporters 1 and 2 (OCT1 and OCT2) ( ). At the apical membrane tenofovir is transported by the multidrug-resistance-related protein 4 (MRP4) and is not transported by the breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or MRP2 ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 4.
Anabolism of the antiherpes drug acyclovir. The first phosphorylation step is efficiently catalyzed by thymidine kinases (TK) of herpesviruses including HSV-1, HSV-2, and varicella-zoster virus ( ). Acyclovir is also inefficiently phos-phorylated by IMP phosphotransferase ( ). The second phosphorylation step is carried out by cellular guanylate kinase ( ). Seven enzymes can catalyze the third phosphorylation step to the active NTP species (in order of efficiency, as follows: phosphoglycerate kinase ≫ pyruvate kinase > phosphoenolpyruvate carboxykinase > nucleoside diphosphate kinase > succinylcoenzyme A synthetase > creatine kinase > adenylsuccinate synthetase) ( ).
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Figure 4.

Anabolism of the antiherpes drug acyclovir. The first phosphorylation step is efficiently catalyzed by thymidine kinases (TK) of herpesviruses including HSV-1, HSV-2, and varicella-zoster virus ( ). Acyclovir is also inefficiently phos-phorylated by IMP phosphotransferase ( ). The second phosphorylation step is carried out by cellular guanylate kinase ( ). Seven enzymes can catalyze the third phosphorylation step to the active NTP species (in order of efficiency, as follows: phosphoglycerate kinase ≫ pyruvate kinase > phosphoenolpyruvate carboxykinase > nucleoside diphosphate kinase > succinylcoenzyme A synthetase > creatine kinase > adenylsuccinate synthetase) ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 5.
Metabolism of 2´-deoxy-2´-fluoro-2´-C-methylcytidine (2´F-2´CMeC) including formation of 2´-deoxy-2´-fluoro-2´-C-methyluridine (2´F-2´CMeU) and its nucleotide metabolites. 2´F-2´CMeC can be phosphorylated sequentially by deoxycyti-dine kinase (dCK), uridylate-cytidylate kinase (UMP-CMP kinase), and NDP kinase (NDPK). 2´F-2´CMeC can also be deaminated by cytidine deaminase to 2´F-2´CMeU, which is not phosphorylated. Deamination by 2´-deoxycytidylate deaminase yields 2´F-2´CMeUMP, which can be phosphorylated by the same pathway as the cytidine nucleotide analog. The scheme summarizes results from prior reports ( ).
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Figure 5.

Metabolism of 2´-deoxy-2´-fluoro-2´-C-methylcytidine (2´F-2´CMeC) including formation of 2´-deoxy-2´-fluoro-2´-C-methyluridine (2´F-2´CMeU) and its nucleotide metabolites. 2´F-2´CMeC can be phosphorylated sequentially by deoxycyti-dine kinase (dCK), uridylate-cytidylate kinase (UMP-CMP kinase), and NDP kinase (NDPK). 2´F-2´CMeC can also be deaminated by cytidine deaminase to 2´F-2´CMeU, which is not phosphorylated. Deamination by 2´-deoxycytidylate deaminase yields 2´F-2´CMeUMP, which can be phosphorylated by the same pathway as the cytidine nucleotide analog. The scheme summarizes results from prior reports ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 6.
Anabolism and catabolism of the anti-HIV drug didanosine (ddI). The first phosphorylation step for ddI is catalyzed by IMP phosphotransferase ( ). The anabolic pathway of ddIMP then overlaps with the de novo synthesis pathway generating ATP including conversion to an AMP analog by adenylsuccinate synthase and lyase and phosphorylation by adenylate kinase and creatine kinase to form the antiviral active metabolite 2´,3´-dideoxyadenosine-TP (ddATP) ( ). ddI is extensively catabolized by a pathway including depurination catalyzed by purine nucleoside phosphorylase (PNP) followed by further metabolism to uric acid by xanthine oxidase (XOD) ( ). Putative sites for the drug interactions resulting in increased exposure to ddI are shown including inhibition of PNP by the phosphorylated metabolites of tenofovir and ganciclovir (GCV) and inhibition of XOD by allopurinol and its metabolite oxypurinol. Figure reprinted from reference with permission ( ).
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Figure 6.

Anabolism and catabolism of the anti-HIV drug didanosine (ddI). The first phosphorylation step for ddI is catalyzed by IMP phosphotransferase ( ). The anabolic pathway of ddIMP then overlaps with the de novo synthesis pathway generating ATP including conversion to an AMP analog by adenylsuccinate synthase and lyase and phosphorylation by adenylate kinase and creatine kinase to form the antiviral active metabolite 2´,3´-dideoxyadenosine-TP (ddATP) ( ). ddI is extensively catabolized by a pathway including depurination catalyzed by purine nucleoside phosphorylase (PNP) followed by further metabolism to uric acid by xanthine oxidase (XOD) ( ). Putative sites for the drug interactions resulting in increased exposure to ddI are shown including inhibition of PNP by the phosphorylated metabolites of tenofovir and ganciclovir (GCV) and inhibition of XOD by allopurinol and its metabolite oxypurinol. Figure reprinted from reference with permission ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 7.
Cidofovir is an acyclic phosphonate analog of 2´-deoxycytidine and does not require the action of a nucleoside kinase for its two-step activation pathway. Cidofovir is first phosphorylated by uridylate-cytidylate kinase (UMP-CMP kinase). Three enzymes can catalyze the second phosphorylation step to the active NTP analog (in order of efficiency as follows: pyruvate kinase > NDP kinase > creatinine kinase). Cidofovir-MP is not a substrate of phosphoglycerate kinase or succinyl-coenzyme A synthetase) ( ).
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Image of Figure 7.
Figure 7.

Cidofovir is an acyclic phosphonate analog of 2´-deoxycytidine and does not require the action of a nucleoside kinase for its two-step activation pathway. Cidofovir is first phosphorylated by uridylate-cytidylate kinase (UMP-CMP kinase). Three enzymes can catalyze the second phosphorylation step to the active NTP analog (in order of efficiency as follows: pyruvate kinase > NDP kinase > creatinine kinase). Cidofovir-MP is not a substrate of phosphoglycerate kinase or succinyl-coenzyme A synthetase) ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 8.
The two major catabolic routes for abacavir are oxidation mediated by alcohol dehydrogenase and conjugation mediated by UDP-glucuronosyltransferase. Human radiolabeled balanced excretion studies have identified the 5´-glucuronide and 5´-carboxylic acid as accounting for 30 and 36% of the dose, respectively ( ). During formation of the 5´-carboxylic acid, the first oxidation step catalyzed by alcohol dehydrogenase and double-bond isomerization have led to the proposal of formation of a reactive Michael acceptor potentially able to form covalent adducts. The metabolic scheme is based on the catabolism of abacavir and the carbocyclic guanosine analog carbovir in vitro ( ).
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Image of Figure 8.
Figure 8.

The two major catabolic routes for abacavir are oxidation mediated by alcohol dehydrogenase and conjugation mediated by UDP-glucuronosyltransferase. Human radiolabeled balanced excretion studies have identified the 5´-glucuronide and 5´-carboxylic acid as accounting for 30 and 36% of the dose, respectively ( ). During formation of the 5´-carboxylic acid, the first oxidation step catalyzed by alcohol dehydrogenase and double-bond isomerization have led to the proposal of formation of a reactive Michael acceptor potentially able to form covalent adducts. The metabolic scheme is based on the catabolism of abacavir and the carbocyclic guanosine analog carbovir in vitro ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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Figure 9.
Structures of nucleoside and nucleotide prodrugs. Famciclovir is the orally bioavailable prodrug of penciclovir in clinical use for herpes. NM 283 and R1626 are prodrugs meant to increase the oral exposure to the experimental anti-HCV nucleosides 2´-C-methylcytidine and 4´-azidocytidine ( ). Adefovir dipivoxil and tenofovir disoproxil are prodrugs that increase the oral bioavailability of the acyclic nucleotide phosphonates adefovir and tenofovir and are used clinically for HBV and HIV therapy, respectively ( ). MB06866 (also known as pradefovir) is an alternate prodrug of adefovir targeted to the liver by cytochrome P450-mediated degradation ( ). GS 9131 is a lymphoid targeted prodrug of a ribose modified nucleotide phosphonate being assessed as an anti-HIV agent ( ).
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Image of Figure 9.
Figure 9.

Structures of nucleoside and nucleotide prodrugs. Famciclovir is the orally bioavailable prodrug of penciclovir in clinical use for herpes. NM 283 and R1626 are prodrugs meant to increase the oral exposure to the experimental anti-HCV nucleosides 2´-C-methylcytidine and 4´-azidocytidine ( ). Adefovir dipivoxil and tenofovir disoproxil are prodrugs that increase the oral bioavailability of the acyclic nucleotide phosphonates adefovir and tenofovir and are used clinically for HBV and HIV therapy, respectively ( ). MB06866 (also known as pradefovir) is an alternate prodrug of adefovir targeted to the liver by cytochrome P450-mediated degradation ( ). GS 9131 is a lymphoid targeted prodrug of a ribose modified nucleotide phosphonate being assessed as an anti-HIV agent ( ).

Citation: Ray A, Hitchcock M. 2009. Metabolism of Antiviral Nucleosides and Nucleotides, p 301-315. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch17
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