Pathways

Zidovudine is a medication used to prevent and to treat HIV/AIDS. It is part of the an antiretroviral and belongs to the NRTI class of drugs, also known as nucleoside reverse transcriptase inhibitors and its generic name is azidothymidine. Zidovudine is generally taken orally, which begins this pathway. After being ingested, Zidovudine is transported into the cell using 6 transporters, namely SLC28A1, SLC28A3, SLC22A6, SLC22A7, SLC22A8, and SLC22A11. After entering the cell, Zidovudine is converted by TK1 to create zidovudine monophosphate. Zidovudine monophosphate is then turned into zidovudine diphosphate through the enzyme DTYMK. Zidovudine diphosphate undergoes a final transformation into zidovudine triphosphate, before being able to perform its intended function and inhibiting HIV RT. Zidovudine also undergoes two other branches of reactions upon entering the cell, the first being catalyzation into 5’-glucuronyl zidovudine, and subsequently being converted by an unknown protein into 3’amino-3’-deoxy-5’-glcopyranuronosylthymidine, which is then eliminated. The second branch of reactions that zidovudine undergoes is its conversion to 3’-amino-3’-deoxythymidine, through the various proteins CYP2C9, CYP2A6, CYP2E1, CYP3A4, and POR, which may or may not be cytotoxic in the cell.

The discovery of AIDS prompted the search for agents that block the HIV replication process. Zidovudine (AZT) is a nucleoside analogue of thymidine, and was shown to reduce considerably the mortality of patients with AIDS. Zidovudine is toxic to the hemtopoietic system, causing anemia and neutropenia. It is clear, however, that disease progression can occur during continued administration of zidovudine. Moreover, zidovudine is not effective in treating Kaposi sarcoma, a common complication of HIV infection. Zidovudine therapy is also associated with a high incidence of toxicity, primarily bone marrow suppression, that requires dosage reduction or discontinuation of the therapy.

Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV) infections. When HIV infects a cell, the virus first binds and fuses with the cell, releasing its nucleocapsid containing its RNA and reverse transcriptase into the cytosol of the cell. The reverse transcriptase converts the viral RNA into viral DNA in the cytosol. The viral DNA goes to the nucleus through the nuclear pore complex where it undergoes the process of transcription. The new viral RNA formed from transcription is transported back to the cytosol through the nuclear pore complex and translation occurs to produce viral proteins. These viral proteins are assembled and new HIV viruses bud from the cell. Zidovudine enters the cell via solute carrier family 22 member 6 and is converted into zidovudine monophosphate by thymidine kinase. Thymidylate kinase then converts zidovudine monophosphate into zidovudine diphosphate. Zidovudine diphosphate is metabolized to zidovudine triphosphate via nucleoside diphosphate kinase A. Zidovudine triphosphate is an analog of deoxyguanosine triphosphate (dGTP). Zidovudine diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its substrate, dGTP and by incorporation into viral DNA. Zidovudine triphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once Zidovudine triphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed. Zidovudine has a high frequency of side effects that limits its use. Side effects of taking zidovudine may include nausea, vomiting, diarrhea, headaches, myalgia, insomnia, bone marrow suppression, peripheral myopathy, elevated liver enzyme, lactic acidosis and hepatotoxicity.

Metabolites of Zileuton are predicted with biotransformer.

Zinc acetate is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Zinc acetate passes through the liver and is then excreted from the body mainly through the kidney.