Pathway Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics

Representation of candidate genes involved in the metabolism of zidovudine and its mechanism of antiviral action.
Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics
abcb1 abcc4 abcc5 abcg2 slc28a1 slc28a3 slc22a6 slc22a7 slc22a8 slc22a11 ugt2b7 tk1 cyp2c9 cyp2a6 cyp2e1 cyp3a4 por dtymk nme zidovudine zidovudine
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Description

Zidovudine (ZDV), also known as AZT (other names Azidothymidine; Aztec; Novo-Azt; Retrovir) is an important drug used for treatment of HIV infection. It belongs to the family of nucleoside analog reverse transcriptase inhibitors (NRTIs) and is structurally related to the endogenous nucleoside thymidine with an azido group in place of the hydroxyl group at the 3' position of the deoxyribose ring. Presence of azido group prevents formation of phosphodiester linkages needed for DNA replication, causing chain termination. This is the mechanism by which ZDV interferes with viral replication. The effectiveness of ZDV in the treatment of HIV infection is due to its selective affinity for HIV reverse transcriptase as opposed to human DNA polymerases.

Pharmacokinetics
The anti-HIV drug zidovudine (3-azido-2',3'-dideoxythymidine) has three important pathways of clearance.

ZDV is a prodrug and must be activated by phosphorylation in lymphocytes to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall clearance. ZDV passes through membranes via passive diffusion or through uptake transporters (SLC28A1, A3; SLC22A6, A7, A8 and A11). [Articles:19953504, 20504255, 3471758]. ZDV is readily transferred from the apical to the basal compartment in the presence of SLC28A3. SLC28A1 is also able to translocate antiviral nucleoside derivatives like ZDV. SLC22A6, SLC22A7, SLC22A8 and SLC22A11 mediate renal ZDV transport [Articles:15651758, 17412768, 11861798, 20504255]. ZDV undergoes intracellular phosphorylation through three cellular kinases Thymidine kinase (primarily 1) is responsible for the conversion of ZDV to ZDV-monophosphate (ZDV-MP), which in turn is converted to ZDV diphosphate (ZDV-DP) through thymidylate kinase, which is the rate limiting step. The conversion of ZDV-DP to the active triphosphate metabolite (ZDP-TP) is mediated by the enzyme nucleoside diphosphate kinase [Articles:2430286, 8690233].

The second metabolic pathway involves inactivation of ZDV by glucouronidation resulting in the formation of 3'-azido-3'-deoxy-5'-D-glucopyranuronosylthymidine (5'-glucuronyl zidovudine; GZDV). GZDV is inactive and approximately 60-70% of the drug is excreted in urine in the glucouronide form [Article:9522101]. Thus indicating that glucuronidation is the predominant pathway in the metabolism of ZDV. Of 11 different UGTs screened, UGT2B7 has been identified as the principal isoform responsible for ZDV glucuronidation [Articles:12920168, 1974193, 8690233].

The third metabolic pathway involves reduction of the azido moiety resulting in formation of 3'-amino-3'- deoxythymidine (AMT). Cytochrome P450s and P450 reductase has been implicated in formation of AMT [Articles:9586947, 1996084, 8053924, 8690233]. Formation of AMT metabolite has been observed in both rat and human liver microsomes [Article:1996084]. AMT has been shown to be about 5- to 7-fold more toxic to human haematopoietic progenitor cells contributing towards cytotoxicity of ZDV in patients.

Renal clearance is an important elimination pathway for antiviral agents and is controlled mostly by membrane transport proteins. Fourteen percent of the parent compound and ~ 74% of the glucouronide form has been recovered in the urine sampled [Article:9522101].

Transporters belonging to ABC family namely ABCB1 (MDR1), ABCC4 (MRP4), ABCC5 (MRP5), and ABCG2 (BCRP) have been implicated in clearance of ZDV [Articles:18364470, 16791115, 15456083, 18535159, 16130519, 20015290, 20504255]. ABCG2 is considered to be a cellular factor that modulates the anti-HIV-1 activity of NRTIs. The ATP binding cassette (ABC) transporter family members, multidrug resistant-1 (MDR-1) and multidrug resistance-associated proteins (MRPs) can efflux both NRTIs and NRTI-monophosphates from intracellular compartments. It has been observed that ZDV increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. [Articles:18364470, 16791115, 15456083, 18535159, 16130519, 20015290, 20504255].

Pharmacodynamics
In viral infected cells, pharmacologically active form of ZDV, zidovudine triphosphate (ZDV-TP) inhibits the activity of HIV-1 reverse transcriptase by competing with its natural nucleotide counterpart thymidine triphosphate for incorporation into newly synthesized viral DNA. Once incorporated, it leads to DNA chain termination and stops further DNA synthesis.

The efficacy of ZDV treatment in HIV infection attributed to its selective affinity for HIV reverse transcriptase as against to human DNA polymerase [Articles:2430286, 2449866] however non-specific inhibition of mitochondrial DNA polymerase gamma results in observed mitochondrial toxicity. Specifically interference of mitochondrial DNA replication by ZDV-TP results in reducing mitochondrial DNA subsequently leading to mitochondrial dysfunction with anaerobic respiration, lipoatrophy, myopathy and lactic acidosis with hepatosteatosis [Articles:16758472, 19740910, 12799554, 15838796, 2320079, 8645849]. These undesirable side-effects are further potentiated in HIV-patients due to negative impact of HIV infection on mitochondria [Article:11893792]. Due to these factors the package insert of ZDV includes warnings for risk of hematological toxicity, myopathy and lactic acidosis with hepatosteatosis a rare but life threatening mitochondrial toxicity [Article:20953318].

Pharmacogenetics
A pilot study addressing pharmacogenetic characteristics of zidovudine therapy in HIV-infected adults reported a trend for elevated zidovudine-triphosphates in ABCC4 G3724A (rs11568695) variant carriers. The median ZDV-triphosphate concentration was 49% higher in subjects carrying at least one variant allele (AG+AA) than those having wild type (GG). ABCB1 (rs2032582) genotype dependent changes in HIV-RNA from baseline to week 52 were observed. Subjects with GT or TT experienced significantly greater reductions in HIV RNA compared to subjects with GG [Article:16791115]. Another study showed a faster oral clearance for ZDV for some UGT2B7 polymorphisms [Article:19628728]. UGT2B7*1c (rs28365062) carriers had 196% higher ZDV oral clearance than noncarriers. Although very few studies have evaluated pharmacogenomics with respect to zidovudine and antivirals overall, results discussed above indicate that genetic variation in the genes coding ZDV metabolism may influence efficacy and toxicity of zidovudine therapy. Future studies in large patient cohorts are needed to further examine and validate the role of pharmacogenomics factors in ZDV pharmacokinetic/pharmacodynamic. Studies focusing on evaluation and identification of genomic factors influencing ZDV pharmacodynamics especially as it relates to mitochondrial toxicity are lacking in literature.

Authors: Yogita Ghodke, Peter Anderson, Katrin Sangkuhl, Jatinder Lamba.
Citation:
Ghodke Yogita, Anderson Peter L, Sangkuhl Katrin, Lamba Jatinder, Altman Russ B, Klein Teri E. "PharmGKB summary: zidovudine pathway" Pharmacogenetics and genomics (2012).
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History:
Therapeutic Categories:
  • Anti-infective agents

Entities in the Pathway

Genes (20)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
5'-glucuronyl zidovudine 3'-amino- 3'-deoxythymidine glucuronide 1996084, 8690233
HIV-RT HIV-RT zidovudine 2430286, 8690233
zidovudine 3'-amino-3'- deoxythymidine CYP2A6, CYP2C9, CYP2E1, CYP3A4, POR 1996084, 8053924, 8690233, 9586947
zidovudine 5'-glucuronyl zidovudine UGT2B7 12920168, 1974193, 8690233, 9522101
zidovudine zidovudine NME1, NME2 2430286, 8690233
zidovudine zidovudine DTYMK 2430286, 8690233
zidovudine zidovudine TK1 2430286, 8690233
zidovudine zidovudine ABCB1, ABCC4, ABCC5, ABCG2 10470083, 15456083, 16130519, 16791115, 18364470, 18535159, 20015290, 20504255
zidovudine zidovudine ABCC4, ABCG2 10470083, 16791115
zidovudine zidovudine SLC22A11, SLC22A6, SLC22A7, SLC22A8, SLC28A1, SLC28A3 11861798, 15651758, 17412768, 19953504, 20504255

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