Morphine glucuronic acid conjugate

Parker RJ, Hirom PC, Millbum P. Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic add in the rat. Hydrolysis of glucuronic acid conjugates in the gut lumen. Xenobiotica 1980 10 689-703. 

Morphine orally is less effective and absorption is very slow. It has variable and high first pass metabolism when given by subcutaneous route, its analgesic effect starts within 10 minutes which persists for 4 to 5 hours and by IV route, it produces immediate action. In plasma, it binds to plasma proteins (approx. 30%). In liver it is metabolized by conjugation to glucuronic acid to form active and inactive products, which are excreted in urine. It is also excreted though bile and in the faeces. 

Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by common tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid. 

After intravenous administration heroin is very quickly metabolized (half-life is about 3 min) into 6-MAM and morphine. The 6-MAM reaches its maximum concentration in 6 min, then transforms itself into morphine, which reaches its peak in 20 min. In the liver and kidneys, deacetylation occurs, but in the liver other reactions also occur N-demethylahon that leads to normorphine, methylation that leads to codeine and conjugation with glucuronic acid. 

Metabolism (C). Like other opioids bearing a free hydroxyl group, morphine is conjugated to glucuronic acid and excreted renally. Glu-curonidation of the OH group at position 6, unlike that at position 3, does not affect af nity for the receptors. 

Conjugation with glucuronic acid is a major elimination route that occurs at the 3-OH and to a lesser extent at the 6-OH of morphine and the 6-OH of codeine. This route accounts for 65% of morphine in urine of humans/430 ... 

Figure 2.23. Metabolism of phenobarbital and of morphine, a Two stage metabolism of phenobarbital. The initial hydroxyla-tion (phase I) creates the anchor for attachment of polar moieties, in this case glucuronic acid (right, top) and sulfate (right, bottom), b Morphine has free OH groups to start with and therefore does not require a phase I reaction. However, in addition to conjugation, desmethylationmay occur.

Morphine may also be metabolised by A -demet-ylation to normorphine. Alkylation to produce codeine (the 3-O-methyl derivative) has also been suggested but more recent work indicates that codeine arises due to the presence of codeine or acetylcodeine as contaminants in morphine or illicit diamorphine preparations. Codeine can be metabolised by the reverse reaction, O-demethylation, to yield morphine, as well as by conjugation with glucuronic acid and N-demethylation. 

Disposition in the Body. Readily absorbed after oral administration or by injection. Rapidly hydrolysed to 6-monoacetylmorphine in blood and then more slowly metabolised to morphine which is the major active metabolite normorphine is also formed to a minor extent small quantities of codeine are occasionally seen in the urine of addicts, but this is thought to arise from the presence of acetylcodeine as an impurity in illicit heroin samples. All metabolites may be conjugated with glucuronic acid. Up to 80% of a dose is excreted in the urine in 24 hours, mainly as morphine-3-glucuronide with about 5 to 7% of the dose as free morphine, 1% as 6-monoacetylmorphine, 0.1 % as unchanged drug, and trace amounts of other metabolites after inhalation, 14 to 20% of the dose appears in the urine morphine metabolites are excreted in the bile. 

Codeine is excreted via the kidneys mainly unchanged or as the conjugate with glucuronic acid. Amounts of norcodeine (10-20%) and morphine (5-15%) considerably exceed the amounts of the other metabolites (normorphine, hydrocodone, dihydrocodeine), which are present only in traces [43,44],... 

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