Nucleoside and nucleotide reverse

Nucleoside and nucleotide reverse transcriptase analogues (NRTI) lack a 3 hydroxyl group and as a result no additional nucleotides can be incorporated into the growing DNA chain. Two NRTI resistance mechanisms are identified impairment of the incorporation of the antiretroviral drug (discrimination) and removal of the analogue from the terminated DNA chain (excision) as reviewed in Chap. 3 (Arion et al. 1998 Meyer et al. 1999 Saralianos et al. 1999). 

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 ... 

These sorbents may be used either for selective fixation of biological molecules, which must be isolated and purified, or for selective retention of contaminants. Selective fixation of biopolymers may be easily attained by regulation of eluent polarity on the basis of reversed-phase chromatography methods. Effective isolation of different nucleic acids (RNA, DNA-plasmid) was carried out [115, 116]. Adsorption of nucleosides, nucleotides, tRN A and DNA was investigated. It was shown that nucleosides and nucleotides were reversibly adsorbed on... 

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. 

Nucleosides and Nucleotides excl. Reverse Transcriptase Inibitors (ribavirin, acidovir, ganciclovir, famciclovir, valacidovir)... 

The specific use of reversed-phase ion-pairing techniques for the simultaneous analysis of purine and pyrimidine bases, nucleosides and, nucleotides has found limited chromatographic application, although it is a technique that warrants further investigation. 

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. 

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... 

Fig. 11.1.4. Separation of uracil and 5-fluorouracil bases, nucleosides and nucleotides by reversed phase ion-pair HPLC. Chromatographic conditions column, Bondapak Cig (300 x 4 mm) mobile phase, (from 0-30 min) 0.1 mM tetrabutylammonium hydrogen sulphate (Cjg), 2.5 mM tetraethylammonium bromide (Cg) and 2% methanol in 2 mM sodium acetate, 1.5 mM phosphate buffer, pH 6.0 (Buffer A) (from 30-50 min) Buffer A-i-30 mM phosphate detection, UV at 254 nm. Peaks FU, fluorouracil FUR, fluorouracU riboside/ FUdR, fluorouracil deoxyriboside FUMP, fluorouridine 5 -monophosphate 5 dFUR, 5 -deoxyfluorouracil riboside FdUMP, deoxyfluorouri-dine monophosphate UDPG, uridine diphosphoglucose UDP, uridine diphosphate dUDP, deoxyuridine monophosphate UTP, uridine triphosphate. Reproduced from Au et al. (1982), with permission.

Mixed-bed supports containing ion-exchange and reversed-phase materials have been u to separate nucleosides and nucleotides (27). A linear relationship between solute retention and support composition was ob-... 

In order to interact with their target enzyme, the reverse transcriptase, pharmacologically effective levels of 2, 3 -dideoxynucleoside-5 -triphosphates have to be generated. This implies that the candidate 2, 3 -dideoxynucleoside has to enter the cell, using the nucleoside transport mechanisms or by passive diffusion. The 2, 3 -dideoxynucleoside must also be transformed to the corresponding 5 -triphosphate by cellular kinases, because HIV does not appear to encode for nucleoside kinases. The efficiency of this phosphorylation strongly depends on the type of compound and the nature of the cells. The susceptibility of the nucleosides and nucleotides involved in this process to metabolic enzymes such as deaminases, hydrolases and phosphatases is another important factor to reach and maintain effective levels of dideoxynucleoside triphosphates. 

Ion-pair reversed-phase h.p.l.c. analyses have been reported for guanine and its nucleosides and nucleotides in human erythrocytes with post-column fluorescence derivatization with phenylglyoxal (a method that is selective for guanine-containing compounds),and adenosine, its breakdown products inosine and hypoxanthine, and dopamine in rat tissue. ... 

Nucleic Compoimds. The chromatographic behavior of nucleic compoimds, i.e., nucleobases, nucleosides, and nucleotides was investigated using reversed phase HPLC on a CIS column (17). Several different mobile phase additives were used, including 1-butyl-3-methylimidazolium tetrafluoroborate, l-ethyl-3-methyhmidazol-ium methylsulfate ionic liquids, ammonium formate, and potassium phosphate. 

The pool of purine bases, nucleosides and nucleotides on body fluids and tissues has been assessed by reversed-phase h.p.l.c. procedures. The relationship between the retention parameters for... 

---