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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 
 

Pharmacological disposition of 1,4-dihydroxy-5-8-bis[[2 [(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride in the dog.

DHAQ, a new antitumor agent, has been selected for clinical trial on the basis of its activity against a number of transplantable rodent tumors. In anticipation of the clinical trial of this agent, the pharmacology of DHAQ was studied in beagles by high-pressure liquid chromatographic and radiochemical techniques that are specific for the unchanged drug. 14C-DHAQ was administered IV to beagles at a dose of 5 mg/kg, 100-125 microCi total. With a maximal plasma concentration of 75 +/- 2.7 ng/ml, DHAQ was eliminated from the plasma with a half-life of 28.1 h during the terminal phase. The total clearance of DHAQ was 10.1 +/- 0.4 mg/kg/min, while the apparent volume of distribution was 26.6 +/- 4.9 l/kg. In 48 h, 2.4% +/- 0.6% of the dose was excreted in the urine and 3.0% +/- 0.1% in the bile as the unchanged drug. At autopsy performed 5 h after dosing, the highest percentage of the administered DHAQ was in the liver (49.7% +/- 2.7%), followed by the small intestine (7.1% +/- 0.7%), kidneys (2.7% +/- 0.1%), lung (1.9% +/- 0.3%), spleen (1.6% +/- 0.3%), and stomach (1.3% +/- 0.1%). The heart, large intestine, pancreas, gallbladder, urinary bladder, and brain each retained less than 1% of the dose. However, 24 h after dosing 10.6% of the drug was detected in the liver and 2.9% in the small intestine. In terms of the percentage of the dose, the distribution of DHAQ in the other organs either remained unchanged or increased slightly. In concentrations varying from 10 ng/ml to 10 micrograms/ml the drug was 70%-80% bound to plasma protein. DHAQ was metabolized to two unidentified metabolites. Thus, this drug appeared to be cleared from the plasma of beagle dogs chiefly by tissue binding, leading to possible persistence of the drug in certain body compartments.[1]

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