Drug metabolism conjugated metabolites

Zenser, T.V., Lakshmi, V.M. and Davis, B.B. (1999) Human and Escherichia coli /3-glucuronidase hydrolysis of glucuronide conjugates of benzidine and 4-aminobiphenyl, and their hydroxy metabolites. Drug Metabolism and Disposition The Biological Fate of Chemicals, 27, 1064—1067. 

Pharmacokinetics Difenoxin is rapidly and extensively absorbed orally. Mean peak plasma levels occur within 40 to 60 minutes. Plasma levels decline to less than 10% of their peak values within 24 hours and to less than 1 % of their peak values within 72 hours. This decline parallels the appearance of difenoxin and its metabolites in the urine. Difenoxin is metabolized to an inactive hydroxylated metabolite. The drug and its metabolites are excreted, mainly as conjugates, in urine and feces. 

Doxorubicin is not absorbed orally, and because of its ability to cause tissue necrosis must not be injected intramuscularly or subcutaneously. Distribution studies indicate rapid uptake in all tissues except the CNS. Extensive tissue binding, primarily intranuclear, accounts for the prolonged elimination half-life. The drug is extensively metabolized in the liver to hydroxylated and conjugated metabolites and to aglycones that are primarily excreted in the bile. 

The chemical reactions involved in drug biotransformation are also classified as either phase I or phase II reactions.27,28 52 60 Phase I reactions consist of those using oxidation, reduction, or hydrolysis. Phase II reactions involve conjugation of the parent drug or the metabolite of a drug that was already metabolized using a phase I reaction. 

Hydrolytic cleavages, along with oxidations, reductions, alkylations, and dealkylations, constitute phase I reactions of drug metabolism. These reactions subsume all metabolic processes apt to alter drug molecules chemically and take place chiefly in the liver. In phase II (synthetic) reactions, conjugation products of either the drug itself or its phase I metabolites are formed, for instance, with glucuronic or sulfuric acid... 

Drug metabolism is commonly - and somewhat arbitrarily - subdivided into phase I and phase II reactions. In Figure 2.22, phase I would correspond to the conversion of a dmg molecule to a more hydrophilic metabolite. The latter may then either be directly excreted in the urine, or undergo conjugation with a larger polar moiety before excretion. 

Sulphate conjugates are formed with hydroxy compounds (e.g. alcohols and phenols) or aromatic amines. For example, morphine-3-(9-ethereal sulphate is a minor metabolite of morphine and N-phenylsulphamic acid is a metabolite of aniline. Sulphate conjugates are strong acids and are readily excreted in the urine they are of relatively little importance in drug metabolism. 

Disposition in the Body. Slowly but completely absorbed following oral administration. It appears to undergo significant first-pass metabolism bioavailability about 70%. After intravenous administration, about 57% of a dose is excreted in the urine and 30% in the faeces over a period of 21 days less than 10% of the dose is excreted as unchanged drug. The principal metabolite is the desmethyl derivative, which has been shown to be active in animals, but hydroxylation also occurs to form phenolic derivatives which may be further converted to aromatic methoxy ethers or excreted as glucuronide conjugates A -oxidation also occurs and maprotiline A -oxide has been reported to be active numerous minor metabolites have been identified in urine. 

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