Intracellular limitations toxicity

Cladribine, or 2-chlorodeoxyadenosine, is resistant to adenosine deaminase and after intracellular phosphorylation by deoxycytidine kinase, it is incorporated into DNA. It is considered the drug of choice in hairy cell leukemia because of high activity combined with acceptable toxicity. Cladribine shows variable oral absorbtion and is usually administered intravenously. Its concentration-time course is biphasic with plasma half-lives of 35 minutes and 6.7 hours. Excretion is primarily by the kidneys. Its most prominent dose-limiting toxicity is myelosup-pression. 

Fludarabine phosphate (2-fluoro-arabinofuranosyladenine monophosphate) is rapidly dephosphorylated to 2-fluoro-arabinofuranosyladenine and then phosphorylated intracellularly by deoxycytidine kinase to the triphosphate. This metabolite interferes with DNA synthesis through inhibition of DNA polymerase- and ribonucleotide reductase, and it also induces apoptosis. Fludarabine phosphate is used chiefly in the treatment of low-grade non-Hodgkin s lymphoma and chronic lymphocytic leukemia (CLL). Fludarabine phosphate is given parentally and is excreted primarily in the urine its dose-limiting toxicity is myelosuppression. 

Viruses are obligate intracellular organisms as their replication is based on DNA and RNA dependent processes and protein synthesis of the host. Antiviral therapy can therefore not be as selective as antibacterial treatments and anti-viral agents tend to inhibit host cell function and can cause major toxicity. An other problem with antiviral therapy is the fact that active viral replication mostly takes place before symptoms become manifest. Our armamentarium against most viral infections is limited. 

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

ACAT transfers amino-acyl groups from one molecule to another. ACAT is an important enzyme in bile acid synthesis, and catalyses the intracellular esterification of cholesterol and formation of cholesteryl esters. ACAT-mediated esterification of cholesterol limits its solubility in the cell membrane and thus promotes accumulation of cholesterol ester in the fat droplets within the cytoplasm this process is important in preventing the toxic accumulation of free cholesterol that would otherwise damage ceU-membrane structure and function. Most of the cholesterol absorbed during intestinal transport undergoes ACAT-mediated esterification before incorporation into chylomicrons. In the liver, ACAT-mediated esterification of cholesterol is involved in the production and release of apo-B-containing lipoproteins. 

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