Codeine 6-glucuronide

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. 

Some Principal route is glucuronidation to codeine-6-glucuronide. Also demethylation. 5-15% of dose converted to morphine by O-demethylation (CYP2D6) First-pass metabolism of 50% Yes. Significant part of analgesic effect thought to be due to conversion to morphine... 

The determination of the heroin metabolites morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G), and 6-monoacetyhnorphine (6-MAM) in body fluids is an important application of LC-MS in the toxicology laboratory. In some cases, codeine and codeine-6-glucuronide are determined as well. Several quantitative methods have been reported. However, only a few deal with forensic toxicology, performing the analysis in urine, serum, vitreous humour [79], and autopsy whole blood [79-80]. 

Fig. 3 Metabolism codeine to the active metabolites morphine and codeine-6-glucuronide, the demethylation to morphine being catalyzed by CYP2D6 morphine is further metabolized to morphine-3-glucuronide and morphine-6-glucuronide...

Heybroek et used PGEs (Ei +0.4 V, E2 +0.9 V vs Pd) in the analysis of codeine and morphine in plasma and gastric juice. Sample preparation was by on-line extraction (ethyl-modified silica column). Codeine-6-glucuronide was measured as codeine after off-line enzymic hydrolysis. Svensson et measured morphine, normorphine and M-6-G as metabolites of codeine using PGEs (Ei +0.25 V, E2 +0.35 V vs Pd) but, because of the low potentials used, the 3-methyl... 

Bogusz MJ, Maier RD, Erkens M, Driessen S. 1997. Determination of morphine and its 3- and 6-glucuronides, codeine, codeine-glucuronide and 6-monoacetylmorphine in body fluids by liquid chromatography atmospheric pressure chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 703 115. 

Figure 1 Frequencies of codeine glucuronidation in Caucasian and Chinese populations. The data are shown in terms of the logarithms of the metabolic ratios in 149 Caucasians and 133 Chinese. Source From Ref. 35.

Other opioids are (the more common street names are in brackets) acetyl codeine buprenorphine codeine (Captain Cody, Cody, and schoolboy) codeine-glucuronide dextromethorphan dextromoramide dihydrocodeine (DHC) EDDP ethylmorphine ... 

Mignat C, Wille U, Ziegler A. (1995). Affinity profiles of morphine, codeine, dihydrocodeine, and their glucuronides at opioid receptor subtypes. Life Sci. 56(10) 793-99. 

Codeine phosphate is still used for diarrhea predominantly based on hypermotility but the longer-acting loperamide is more convenient and has less central nervous system effects. Codeine has an exceptionally low affinity for opioid receptors and its effects are due to the fact that it is converted for approximately 10% to morphine. The active metabolite of morphine, morphine-6-glucuronide, may also accumulate during repeated administration of codeine to patients with impaired renal function. 

Morphine is glucuronidated in the liver at the phenolic hydroxyl group (C3). Protection of that group with a methyl group, as occurs in codeine and other codeine derivatives such as oxycodone, renders the molecule less susceptible to glucuronidation and decreases the first-pass effect in the liver. It is for this reason that codeine and its derivatives retain activity following oral... 

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 Ethylmorphine (Aasmundstad et al., 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O- and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides. 

Yue, Q.Y., Aim, C., Svensson, J.O., Sawe, J. Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators, Ther. Drug Monit. 1997, 19, 539-542. 

C. P. W. G. M. Verwey-Van Wissen and P. M. Koopman-Kimenai, Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by HPLC with electrochemical detection, J. Chromatogr., 570 309(1991). 

Svensson JO, Andersson M, Gustavsson E, Beck O (2007) Electrospray LC-MS method with solid-phase extraction for accurate determination of morphine-, codeine-, and ethylmorphine-glucuronides and 6-acetylmorphine in urine. J Anal Toxicol 31(2) 81-86... 

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. 

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