Daunorubicin metabolism

The anthracyclines, apart from valrubicin, are administered intravenously. Doxorubicin is rapidly distributed to tissues and slowly eliminated in faeces and urine with an elimination half-life of several days. Daunorubicin undergoes extensive metabolism in the liver, among others to the active daunorubi-cinol, and is eliminated as inactive products with an elimination half-live of approximately 30 hours. Epimbicin and idambicin have similar kinetic profiles as daunombicin with respectively epirubici-nol and idarubicinol as their major metabolic products. The kinetic behavior of mitoxantrone resembles more that of doxorubicin with a very slow elimination from the body mainly as parent compound or as inactive metabolites. The anthracyclines do not cross the blood-brain barrier. 

Idarubicin (Idamycin) differs from its parent compound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mechanisms of action and resistance are similar to those of doxorubicin and daunorubicin however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabolism and biliary excretion. Adverse reactions of idarubicin are similar to those of its congeners. 

DAUNORUBICIN AZATHIOPRINE t risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity Avoid co-administration... 

The long terminal plasma half-life of daunorubidn results from extensive tissue binding. It is readily metabolized to daunorubicinol hy reduction of its l. -keto gniup. This metabolite is one-tenth ns active as daunorubicin. The drug and its metabolite are eliminated hy hepatobiliary excretion. 

Absorption, fate, and excretion Daunorubicin, doxom-bicin, epirubicin, and idarubicin usually are administered intravenously and cleared by a complex pattern of hepatic metabolism and biliary excretion. The plasma disappearance curve for doxorubicin is multiphasic, with elimination half-lives of 3 hours and about 30 hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. Idarubicin has a half-life of about 15 hours, and its active metabolite, ida-rubicinol, has a half-life of about 40 hours. There is rapid uptake of the drugs in the heart, kidneys, lungs, liver, and spleen. They do not cross the blood-brain barrier. 

Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. Idarubicin is primarily metabolized to idarubicinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with abnormal serum bilirubin levels. 

Pharmacokinetics Doxorubicin and daunorubicin must be given intravenously. They are metabolized in the liver, and the products are excreted in the bile and the urine (the red color is not hematuria). 

Various studies regarding the biotransformation of xenobiotic ketones have established that ketone reduction is an important metabolic pathway in mammalian tissue. Because carbonyl compounds are lipophilic and may be retained in tissues, their reduction to the hydrophilic alcohols and subsequent conjugation are critical to their elimination. Although ketone reductases may be closely related to the alcohol dehydrogenases, they have distinctly different properties and use NADPH as the cofactor. The metabolism of xenobiotic ketones to free alcohols or conjugated alcohols has been demonstrated for aromatic, aliphatic, alicyclic, and unsaturated ketones (e.g., naltrexone, naloxone, hydromorphone, and daunorubicin). The carbonyl reductases are distinguished by the stereospecificity of their alcohol metabolites. 

Stutzman-Engwdl KJ, Otten S, Hutchinson CR (1992) Regulation of secondary metabolism in Streptomyces spp. and overproduction of daunorubicin in Streptomyces peucetius. 

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