Morphine demethylation

Nonresponse to codeine (PMs of CYP2D6 fail to O-demethylate to morphine)... 

Metabolism Glucuronidation N-demethylation Ester hydrolysis to morphine Glucuronidation demethylation (CYP2D6) Ester hydrolysis N-demethylation N-Dealkylation, then hydroxylation N-Demethylation Plasma and tissue esterases... 

Pai HV, Kommaddi RP, Chinta SJ, Mori T, Boyd MR, et al. 2004. A frame-shift mutation and alternate splicing in human brain generates a functional form of the pseudogene, cytochrome P4502D7 that demethylates codeine to morphine. J Biol Chem 279 27383-27389. 

The A -demethylation pathway is common to the metabolism of Ml 25 (Vllf) and morphine, both drugs being converted to secondary amines by liver micro-somes under the same condition [55]. Reaction rates were depressed when microsomes from rats repeatedly treated with Ml25 or morphine were used. In the same work, rats were-shown to become tolerant to the pharmacological effects of M125 (shock avoidance and tail clip tests) and cross tolerance to morphine was also found. 

Nalorphine Nalorphine, N-allylnormorphine (3.1.75), is synthesized from morphine by its complete acetylation, i.e. by transformation into heroin (3.1.21), in order to temporarily protect the hydroxyl groups, and then by undergoing demethylation. In order to do this, heroin (3.1.21) is processed with cyanogen bromide. The resulting N-cyano derivative (3.1.73) is hydrolyzed by a solution of hydrochloric acid into the N-demethylated morphine, normorphine (3.1.74), whose secondary amine group undergoes alkylation with allylbromide to give desired nalorphine [47,48]. 

Initially Robinson and Sugasawa (8) proposed that laudanosoline (5), prepared from laudanosine (4) by O-demethylation with aluminium chloride in refluxing xylene, could be oxidized to an aporphine or morphine prototype. To demonstrate that no rearrangement had occurred, 4 was regenerated from 5 by O-methylation. Oxidation of 5 was accomplished with chloranil in buffered alcohol solution, and 6 was isolated in 60% yield as the chloride (Scheme 1). Di-benzopyrrocoline 6 was also obtained in 30-50% yield when aqueous solutions... 

The most important other opium alkaloid is codeine. In contrast to morphine, codeine has a high oral-parenteral potency ratio due to less first-pass metabolism. Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Approximately 10% is demethylated to morphine. The analgesic effect of codeine is due to the formation of these metabolites as codeine itself has a very low affinity for opioid receptors. The half-life of codeine in plasma is 2 hours. 

Like morphine, meperidine has an active metabolite, normeperidine, formed by A-demethylation of meperidine. Normeperidine is not analgesic but is a proconvulsant and a hallucinogenic agent. For this reason, meperidine use in patients with renal or fiver insufficiency is contraindicated because of the decreased clearance of the drug and its metabolite. Convulsant activity has been documented in elderly patients given meperidine and in patients using PCA who have decreased renal function. 

Ethyl morphine N-demethylation nmol HCHO 100g 1 body weight 10 min-1... 

The pharmacological action of codeine is increased by induction as this increases demethylation to morphine. Induction by phenobarbital decreases the toxicity of organo-phosphates, but increases that of phosphorothionates. Studies with the drug warfarin have shown that induction by both phenobarbital and 3-methylcholanthrene will change the stereochemistry of the product, as can be seen in Table 5.24. Thus, hydroxylation in the 8-position in the R-isomer is increased 12 times compared with only 4 times with the S-isomer following 3-methylcholanthrene induction. 

Opioid receptor binding Codeine has a low affinity at j-, 5-, and K-opioid receptors and the in vivo effects are predominantly induced by morphine, formed by metabolic O-demethylation. 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Pethidine (Mather and Meffin, 1978) has a faster onset and a shorter duration of action than morphine. After oral administration about 50% of the drug is eliminated by first-pass metabolism. N-demethylation yields the active metabolite nor-pethidine, and hydrolytic cleavage the inactive metabolites pethidinic and nor-pethidinic acid. The half-life of pethidine is about 3- 6 h. Nor-pethidine has a much slower elimination with a half life of up to 20 h. 

A small amount of morphine, on the order of 5%, is N-demethylated by hepatic CYP3A4, and to a lesser extent CYP2C8, to form normorphine 27 This metabolite itself has pharmacological activity, but it is less potent than morphine and is present in lower concentrations. 

Projean, D., P.E. Morin, T.M. Tu, and J. Ducharme, Identification of CYP3A4 and CYP2C8 as the major cytochrome P450s responsible for morphine jV-demethylation in human liver microsomes,... 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

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