Excretion nucleosides

Since no human enzyme catalyzes hydrolysis or phos-phorolysis of pseudouridine, this unusual nucleoside is excreted unchanged in the urine of normal subjects. 

Figure 10.8 A summary of the reactions involved in the degradation of nucleic acid, nucleotides, nucleosides and purine and pyn midine bases. Nucleic add is hydrolysed by nucleases to form nucleotides, which are hydrolysed to nucleosides. The latter are split into ribose 1-phosphate and a base. The purine bases are converted to uric acid and ammonia. Uric acid is excreted. The pyrimidine bases are converted to 3-carbon intermediates (malo-nate semialdehyde and methylmalonate semialdehyde). The nitrogen is released as ammonia or used to convert oxoglutarate to glutamate.

Mechanism of Action Apurine nucleoside analog that is intracellularly converted into a triphosphate, which interferes with RNA-directed DNA polymerase (reverse transcriptase). Therapeutic Effect Inhibits replication of retroviruses, including HIV. Pharmacokinetics Variably absorbed from the GI tract. Protein binding less than 5%. Rapidly metabolized intracellularly to active form. Primarily excreted in urine. Partially (20%) removed by hemodialysis. Half-life 1.5 hr metabolite 8-24 hr. 

Mechanism of Action A synthetic nucleoside that inhibits influenza virus RNA polymerase activity and interferes with expression of messenger RNA. Therapeutic Effect Inhibits viral protein synthesis and replication of viral RNA and DNA. Pharmacokinetics Rapidly absorbed from the GI tract following oral administration. A small amount is systemically absorbed following inhalation. Primarily excreted in urine. Half-life 298 hr (oral) 9.5 hr (inhalation). 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

Figure 25-18 Pathways of catabolism of purine nucleotides, nucleosides, and free bases. Spiders excrete xanthine while mammals and birds excrete uric acid. Spiders and birds convert all of their excess nitrogen via the de novo pathway of Fig. 25-15 into purines. Many animals excrete allantoin, urea, or NH4+. Some legumes utilize the pathway marked by green arrows in their nitrogen transport via ureides.

Low activities of orotidine phosphate decarboxylase and (usually) orotate phosphoribosyltransferase are associated with a genetic disease in children that is characterized by abnormal growth, megaloblastic anemia, and the excretion of large amounts of orotate. When affected children are fed a pyrimidine nucleoside, usually uridine, the anemia decreases and the excretion of orotate diminishes. A likely explanation for the improvement is that the ingested uridine is phosphorylated to UMP, which is then converted to other pyrimidine nucleotides so that nucleic acid and protein synthesis can resume. In addition, the increased intracellular concentrations of pyrimidine nucleotides inhibit carbamoyl phosphate synthase, the first enzyme in the. naibwav of aro-tate synthesis. 

As far as quantitative chemical derivatization GC analysis is concerned, it is necessary to mention especially the work of Gehrke and his collaborators, who specified the fundamental concepts of quantitative GC analysis combined with the chemical derivatization of sample compounds and applied them to the accurate determination of the twenty natural protein amino acids and other non-protein amino acids as their N-TFA-n-butyl esters [5 ], the urinary excretion level of methylated nucleic acid bases as their TMS derivatives [6], TMS nucleosides [7] and other investigations. Further examples include a computer program for processing the quantitative GC data obtained for seventeen triglyceride fatty acids after their transesterification by 2 NKOH in n-butanol [8], a study of the kinetics of the transesterification reactions of dimethyl terephthalate with ethylene glycol [9] and the GC-MS determination of chlorophenols in spent bleach liquors after isolation of the chlorophenols by a multi-step extraction, purification of the final extract by HPLC and derivatization with diazoethane [10]. 

Bu HZ, Pool WF, Wu EY et al. (2004). Metabolism and excretion of capravirine, a new non-nucleoside reverse transcriptase inhibitor, alone and in combination with ritonavir in healthy volunteers. Drug Metab Dispos 32 689-698... 

TRIMETHOPRIM NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Possibly t haematological toxicity Competition for renal excretion Monitor FBC and renal function closely... 

FOSCARNET SODIUM NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS - LAMIVUDINE, TENOFOVIR, ZALCITABINE t adverse effects with tenofovir and possibly lamivudine and zalcitabine Uncertain possibly additive toxicity via competition for renal excretion Avoid if possible otherwise monitor FBC and renal function weekly... 

In addition to major nucleosides and bases, modified nucleosides and bases have also been isolated from tRNA hydrolysates and in physiological fluids of man. Unlike the major nucleic acid components, the methylated or otherwise structurally altered purine and pyrimidine compounds are not recycled in the salvage pathways but are excreted. It has been suggested that the measurement of these modified compounds may provide an indicator of the rate of tRNA metabolism. Furthermore, the altered patterns of excretion for these compounds may be used as biomarkers for the detection of disease states and aberrations in metabolic pathways. 

Nucleosides are metabolites of ribonucleic acid (RNA). As a result of excessive turnover of RNA, which occurs in such pathological conditions as cancer, inflammation, and AIDS, nucleosides are excreted into urine in increased amounts. Normal nucleosides (adenosine, guanosine, cytidine, uridine) either undergo further degradation into uric acid, p-alanine, or p-aminoisobutyrate or are reutilized. On the other hand, modified nucleosides, especially methylated nucleosides, are excreted unchanged in urine. Therefore, it seems that elevated levels of modified nucleosides could be an indicator of the presence of cancer and used as a diagnostic tool in cancer prognosis [23]. 

Urinary excretion of modified nncleosides, originating from tiansfer-RNA, may be nsed as a biomarker for tnmonrs and AIDS. Dudley et al. [54-57] reported method development for the analysis of urinary nucleosides by LC-MS. Initially, LC-MS conditions were optimized [54]. In positive-ion ESI-MS, detection limits were achieved ranging from 7 pmol for tubercidin to 110 pmol for uridine. Next, a comparison was made between GC-MS, LC-MS on an ion-trap instrament, and capillary LC-MS on a triple-quadmpole instmment [55]. These methods proved complementary rather than that just one could be selected as optimal. Therefore, in the next study [56], all three techniques were applied to identily the unexpected 5 -deoxycytidine in the urine of a patient suffering with head and neck cancer. In another study [57], they demonstrated the detection of dA, 1-methyl-dA, xanthosine, 7V-l-methyl-dG, 7V-2-methyl-dG, 7V-2,7V-2-dimethyl-dG, A-2,7V-2,A-7-trimethyl-dG, inosine, and 1-methylinosine in urine samples from various cancer patients. 

Uric acid (UA) is the primary end product of catabolism of purine nucleosides adenosine and guanosine and has often been regarded as a key biomarker in evaluation of physiological wellbeing [157,158], In healthy human, UA is filtered and removed from the blood by the kidneys and excreted through urine and hence kidney diseases are known to affect uric acid... 

In humans, uric acid (2,6,8-trihydroxypurine) is the major product of the catabolism of the purine nucleosides adenosine and guanosine (Figure 24-3), Purines from catabolism of dietary nucleic acid are converted to uric acid directly. The bulk of purines excreted as uric acid arise from degradation of endogenous nucleic acids. The daily synthesis rate of uric acid is approximately 400 mg dietary sources contribute... 

The OAT proteins play a critical role in the excretion and detoxification of a wide variety of drugs, toxins, hormones and neurotransmitter metabolites. A number of common non-steroid anti-inflammatory drugs (NSAID), including acetyl salicylate and salicylate, acetaminophen, diclofenac, ibuprofen, ketoprofen, indomethacin, and naproxen, are substrates of one or more OAT isoforms, so that there can be significant interactions between NSAlDs and other drugs. The 3-lactam antibiotics (penicillins, cephalosporins and penems) and the antiviral nucleosides adefovir, cidofovir,... 

Nucleosides in human urine are often used as biomedical markers for cancer diagnosis and therapy (1-3). It has been studied that nucleosides are excreted... 

CM-induces intrarenal hypoxia, possibly related to the hemodynamic changes and/or increased tubular energy expenditure in response to osmotic stress [33]. It has been proposed that increased renal adenosine levels arising from enhanced ATP hydrolysis may be a major contributor to development of acute renal failure after CM apphcation (Figure 1). This is corroborated by the finding that apphcation of CM increases urinary adenosine excretion [44, 45] and the observation that dipyridamol, a nucleoside uptake blocker, magnifies the renal hemodynamic effects of CM [44, 45]. In addition, there are many similarities between... 

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