Drug metabolism morphine

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. 

Court, M.H., Krishnaswamy, S., Hao, Q., Duan, S.X., Patten, C.J., von Moltke, L.L. and Greenblatt, D.J. (2003) Evaluation of 3 -azido-3 deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes specificity and influence of the UGT2B72 polymorphism. Drug Metabolism and Disposition The Biological Fate of Chemicals, 31, 1125—1133. 

Chemical studies on drug metabolism. IV. Synthesis and analgesic activity of morphine-7,8-oxide and heroin-7,8-oxide... 

Drugs that reduce hepatic blood flow, eg, propranolol, may also reduce the clearance of other drugs metabolized in the liver, especially those subject to flow-limited hepatic clearance such as morphine and verapamil. 

Methylation is often a minor pathway of drug metabolism for some molecules, but enzymes are known which can convert normorphine to morphine [114—115], catechols to methoxycatechols [116] and normeperidine, nor-codeine, and norcornitine to their Af-methyl derivatives. The methyl donor for these Af-methyl transferases is 5-adeno.sylmethionine. 

It is also important to realize that drug metabolism does not necessarily result in detoxication. Indeed, many drugs are converted to metabolites that are as active as or even more active than the parent compound. For example, the conversion of morphine to normorphine in the body is not associated with any significant change in biological activity, whereas the transformation of parathkm to paraoxon represents the conversion of a pharmacologically inactive compound to a potent cholinesterase inhibitor (see Sect. B, Chap. S.l). 

In adult rats, the magnitude of the sex difference in microsomal drug metabolism is dependent upon the drug substrate examined. Microsomes from male rats are 3 to 4 times as active as those from females in the metabolism of ethyl-morphine, hexobarbital, and aminopyrine, but only about twice as active in the metabolism of cocaine or p-nitroanisole. There is no appreciable sex difference in the metabolism of zoxazolamine or aniline by rat-liver microsomes nor in the duration of zoxazolamine paralysis in vivo. Similarly, there is very little sex difference in the cytochrome P-4S0 content or in NADPH cytochrome c reductase activity. 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

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