Nucleoside and nucleotide reverse transcriptase inhibitors

The pharmacokinetics of lamivudine are described earlier in this chapter (see section, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV cell lines (17-19 hours) than in HIV-infected cell lines (10.5-15.5 hours) allows for lower doses and less ffeguent administration. Lamivudine can be safely administered to patients with decompensated liver disease. 

Raltegravir, or Isentress (1), is the first FDA-approved inhibitor of HIV integrase. HIV/AIDS drugs are categorized according to their mode of action as nucleoside and nucleotide reverse transcriptase inhibitors [NRTIs, e.g., tenofovir (2)], nonnucleotide reverse transcriptase inhibitors [NNRTIs, e.g., efavirenz (3)] protease inhibitors [Pis, e.g., ritonavir (4)], fusion inhibitors [e.g., enfuvirtide (5)], entry inhibitors... 

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Qin Ther 2000 22 ... 

Pharmacokinetic Properties of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors ... 

The HIV-encoded, RNA-dependent DNA polymerase, also called reverse transcriptase, converts viral RNA into proviral DNA that then is incorporated into a host cell chromosome. Inhibitors of this enzyme are either nucleoside/nucleotide analogs or nonnucleoside inhibitors (Figure 50-2 and Table 50-2). Like aU available antiretroviral drugs, nucleoside and nonnucleoside reverse transcriptase inhibitors prevent infection of susceptible cells but have no impact on cells that already... 

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

Tenofovir is a nucleotide (nucleoside monophosphate) analogue reverse transcriptase inhibitor, given as a prodrug, tenofovir disoproxU fumarate. In contrast to the other members of this class, it only needs to be phosphorylated twice intraceUularly before it is pharmacologically active. Adverse effects have been reported as flatulence, raised transaminases, raised creatine kinase activity, and rarely a raised serum creatinine (1). Tenofovir does not currently appear to be nephrotoxic. 

Tavel JA, Miller KD, Masur H. Guide to major clinical trials of an-tiretrovhal therapy in human immunodeficiency virus-infected patients protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse hanscriptase inhibitors. Chn Infect Dis 1999 28 643-676. 

Non-nucleoside RTIs that do not require metabolic activation (eg, delavirdine and nevirapine, efavirenz, which are not myelosuppressants) and a nucleotide reverse-transcriptase inhibitor (adefovir) have been introduced. Resistance emerges rapidly if these drugs are used as individual agents for management of HIV infection. However, they may provide additive or synergistic activity against HIV if used in combination regimens with NRTIs and/or Pis. 

Nucleosides, nucleotides, peptidomimetics, and reverse transcriptase inhibitors in HIV infection therapy 98CCC449. 

Reverse transcriptase inhibitors are of two types those that are derivatives of purine- and pyrimidine-based nucleosides and nucleotides (NtRTIs) and those that are not nucleoside or nucleotide based (NNRTIs). 

Gallant JE, Gerondelis PZ, Wainberg MA, Shulman NS, et al. 2003. Nucleoside and nucleotide analogue reverse transcriptase inhibitors A clinical review of antiretroviral resistance. Antivir Ther. 8 489-506. 

Nucleoside reverse transcriptase inhibitors NRTIs are substrates for reverse transcriptase, which converts viral RNA into proviral DNA for incorporation into the host cell DNA. NRSIs are phosphorylated by host ceU enzymes to resemble normal nucleotides. When reverse transcriptase uses NRTI triphosphate instead of a nucleoside to form proviral DNA, the necessary chemical bonds cannot form and the DNA chain formed is left incomplete. 

Nucleosides can be analysed by conventional reversed-phase (RP) LC with a buffered mobile phase. The separation of nucleotides is somewhat complicated by the dissociation of the phosphate groups and HINa exchange at these sites. As indicated for the phosphorylated anabolites of nucleoside reverse transcriptase inhibitors (NRTI, Ch. 13.2.4), ion-pair RPLC using 7V,7V-dimethylhexylamine (DMHA) can be applied to both reduce adduct formation and obtain sufficient retention [6-7]. Alternatively, enzymatic dephosphorylation of the nucleotides prior to LC-MS analysis can be performed. 

RT). This viral protein is the target of narrow spectrum but rather specific inhibitors with reduced toxicity profiles. Nucleoside reverse transcriptase inhibitors (NRTls) are nucleoside analogues competing with the natural substrate of RT. Three consecutive phosphorylations are required for the activity of NRTls, but the first is generally considered as the most difficult and prompted the development of mono-phosphorylated analogues (i.e. nucleotide derivatives). If phosphate and phosphonate derivatives are well represented, the phosphinates are still rarely encountered as phosphate surrogate in this series. 

In parallel, non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit RT by a non-competitive binding to an allosteric site closely located to the catalytic site [18]. The short distances separating the allosteric and the binding sites suggest that NNRTIs alter the function of RT and directly disturb the interactions between the nucleotide natural substrates and the active site. 

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