Zalcitabine 5 -triphosphate

Metabolism/Excretion Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine triphosphate are too low for quantitation. Metabolism has not been fully evaluated. Zalcitabine does not appear to undergo a significant degree of metabolism by the liver. Renal excretion appears to be the primary route of elimination, and accounted for approximately 70% of an orally administered dose within 24 hours after dosing. The mean elimination half-life is 2 hours. Total body clearance following an IV dose averages 285 mL/min. Less than 10% of a dose... 

Pharmacology Zalcitabine, active against HIV, is a synthetic pyrimidine nucleoside analog of the naturally occurring nucleoside deoxycytidine in which the 3 -hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5 -triphosphate (ddCTP), by cellular enzymes. ddCTP inhibits the activity of the HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine 5 -triphosphate (dCTP), and by its incorporation into viral DMA. 

After oral administration, the bioavailability of zalcitabine is more than 80%. Food slightly interferes with its absorption. Sixty to eighty percent of the compound is excreted unchanged in the urine. Its (dideoxycytidine S -triphosphate) peak concentrations are at 2-3 h. The primary metabolite is dideoxyuridine, which is <15% of the administered dose. Zalcitabine is indicated in combination with other antiretroviral agents for the treatment of HIV infection. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Antiretroviral nucleoside analogues have been associated with hepatic steatosis and lactic acidosis. These compounds require phosphorylation to active triphosphate derivatives by cellular phosphokinases. The triphosphate nucleotide inhibits the growing proviral DNA chain, but it also inhibits host DNA polymerases, and this can result in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, and this manifests as hepatomegaly with macrovesicular steatosis. Hepatic steatosis and lactic acidosis have been reported previously with zidovudine, didanosine, zalcitabine, Combivir (zidovudine plus lamivudine), and lamivudine. 

Nudeoside analogue reverse transcriptase inhibitors (NRTls) were the first drugs developed for treatment of HIV infection. They are structural analogues of nucleic adds. When phosphorylafed intraceUularly to their triphosphate forms, fhey are competitive inhibitors of viral reverse franscripfase. Drugs in this class indude abacavir, adefovir, didanosine, lamivudine, sta-vudine, tenofovir, zalcitabine, and zidovudine. 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, zalcitabine, and didanosine which has also been attribute to mitochondrial DNA toxicity [82-93]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, zalcitabine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [78-80, 87, 92-94, 94a]. The link between NRH effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

The oral bioavailability of zalcitabine is greater than 80%, and 60 to 80% of the parent compound is recovered unchanged in the urine. Food has a negligible effect on oral bioavailability. Clearance is greatly diminished in patients with compromised renal function, and daily doses should be reduced in this population. The half-life of intracellular dideoxycytidine 5 -triphosphate is estimated to be 2 to 3 hours. It is therefore recommended that zalcitabine be administered every 8 hours in patients with normal renal function. The CSF-plasma concentration ratio ranges from 0.09 to 0.37, although the clinical significance of CSF penetration is not known. 

Zalcitabine is a synthetic cytosine analog reverse transcriptase inhibitor that is active against HIV-1, HIV-2, and hepatitis B virus. After entering the cell, it is phosphorylated to its active anabohte, dideoxycytidine-5 -triphosphate. In addition to DNA polymerase j, zalcitabine also weakly inhibits DNA polymerase /5. 

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