Codeine analgesia is due to codeine-6-glucuronide, not morphine.

Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype.

Pharmacokinetics of epidurally administered nicomorphine with its metabolites and glucuronide conjugates in patients undergoing pulmonary surgery during combined epidural local anaesthetic block and general anaesthesia.

After epidural administration of 15 mg 3, 6-dinicotinoylmorphine (nicomorphine) in 10 patients undergoing pulmonary surgery, the parent compound was quickly metabolized into the metabolites 6-mononicotinoylmorphine and morphine. The mean apparent half-lives (+/- SD) of elimination were 10 min (0.165 h +/- 0.053 h) for 3,6-dinicotinoylmorphine and 1.77 h +/- 1.23 h for 6-mononicotinoylmorphine. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The apparent half-lives of morphine, morphine-3-glucuronide, and morphine-6-glucuronide are similar: 3.63 h +/- 1.63 h, 4.10 h +/- 0.57 h, and 4.20 h +/- 1.64 h respectively. The possible glucuronide conjugate of 6-mononicotinoylmorphine was not detected. The prodrug 3,6-dinicotinoylmorphine was biotransformed into three active compounds: 6-mononicotinoylmorphine, morphine, and morphine-6-glucuronide.

The bioavailability of intramuscularly administered nicomorphine (Vilan) with its metabolites and their glucuronide conjugates in surgical patients.

The kinetics of 20 mg nicomorphine intramuscularly were described in 8 patients under combined general and epidural anesthesia. The half-life of nicomorphine was 0.32 +/- 0.20 h (mean +/- SD) and is governed by the absorption-rather than the elimination rate. The half-life of 6-mononicotinoylmorphine (0.39 +/- 0.09 h) was identical to that of the parent compound (p = 0.29), suggesting it is directly related to the absorption rate of nicomorphine. Morphine had a half-life of 1.38 +/- 0.31 h. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The half-life of these 2 glucuronide conjugates was about 2.6 h (p = 0.07). A glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In urine only morphine and its glucuronides are found, with renal clearance values of 214 ml.min-1 for morphine and 132 ml.min-1 for the glucuronides. The bioavailability of this pharmaceutical formulation after intramuscular administration equals that of intravenous administration in surgical patients (at the same dose).

Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates.

The pharmacokinetics of 30 mg nicomorphine after rectal administration with a suppository are described in 8 patients under combined general and epidural anaesthesia. No nicomorphine or 6-mononicotinoylmorphine could be detected in the serum. Morphine appeared almost instantaneously with a lag-time of 8 min and had a final elimination half-life of 1.48 +/- 0.48 h. Morphine was metabolized to morphine-3-glucuronide and morphine-6-glucuronide. These glucuronide conjugates appeared after a lag-time of 12 min and the half-life of these two glucuronide conjugates was similar: about 2.8 h (P > 0.8). The glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In the urine only morphine and its glucuronides were found. The renal clearance value for morphine was 162 ml.min-1 and for the glucuronides 81 ml.min-1. This study shows that administration of a suppository with 30 mg nicomorphine gives an excellent absolute bioavailability of morphine and its metabolites of 88%. The lipid-soluble prodrug nicomorphine is quickly absorbed and immediately hydrolysed to morphine.

Morphine and morphine-glucuronide concentrations in plasma and CSF during long-term administration of oral morphine.

Concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from 16 patients with cancer receiving oral (controlled-release) morphine. There was a close correlation between plasma and CSF morphine concentrations (r = 0.94, P = 0.0001) and both correlated with drug dosage (r = 0.61, P = 0.013 and r = 0.74, P = 0.0001, respectively). M3G and M6G in plasma and CSF were correlated (r = 0.81 and r = 0.82, both P = 0.0001). No relationship was apparent between M plus M6G concentrations in the CSF and pain scores.

Pharmacokinetics of intravenously administered nicomorphine and its metabolites in man.

Intravenous doses of 30, 20 and 10 mg nicomorphine (Vilan) are extremely quickly metabolized into the metabolites 6-nicotinoylmorphine and morphine. The half-lives of elimination are respectively 3 min for nicomorphine, 3 and 15 min for 6-nicotinoylmorphine, and 135-190 min for morphine. The kinetics of the 30 and 20 mg dose are comparable, the 10 mg dose shows patient dependent variations in metabolism. The AUC of the parent drug and its metabolites is linearly related to the dose.

Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electrochemical detection.

A high-performance liquid chromatographic method has been developed for the detection, separation and measurement of codeine and its metabolites norcodeine, morphine and normorphine, with their glucuronide conjugates. The glucuronidase Escherichia coli type VIIA hydrolyses codeine-6-glucuronide completely and is used for the construction of the calibration curves of codeine-6-glucuronide. Enzymic hydrolysis of codeine-6-glucuronide depends on the specific activity of the glucuronidase applied. Examples are shown of a volunteer who is able to form morphine from codeine and one who is unable to do so.

Pharmacokinetics of nicomorphine and its metabolites in man after epidural administration.

In ten patients who received an epidural injection of 15 mg of nicomorphine, the compound was relatively slowly released from the epidural space and was found in plasma for approximately 1.5 h. Nicomorphine is relatively slowly metabolized into 6-nicotinoylmorphine and morphine. The rate of release is patient-dependent. The relative AUC values are 15.3% for nicomorphine, 23.9% for 6-nicotinoylmorphine and 60.8% for morphine. The mean clinical effect lasts for 18.2 +/- 10.1 h.

Pharmacokinetics of intramuscular nicomorphine and its metabolites in man.

After i.m. injection nicomorphine is relatively slowly absorbed from the muscular depot and is found in the serum for approximately 1 h. The rate of absorption differs between patients and governs the overall pharmacokinetic profile of the compound. The relative AUCs were nicomorphine 18%, 6-nicotinoylmorphine 17%, and morphine 65%. Nicomorphine and 6-nicotinoylmorphine have significantly higher AUCs after i.m. injection than after i.v. injection, while the AUC of morphine and the total AUC show no difference between the two modes of administration.

High-performance liquid chromatography of xanthines. Effects of N-methyl and C-8 hydroxyl substitution on the retention times.

The capacity factors of 26 xanthine derivatives were measured by reversed-phase high-performance liquid chromatography. N-Methyl substitution increased the capacity factor and the related lipid solubility. The descending order of the increase in capacity factor by the N-methyl group is: N-1 methyl greater than N-3 methyl greater than N-7 methyl greater than N-9 methyl. C-8 hydroxylation reduces the capacity factor in the xanthines. The reduction factor is 3.34 in xanthines with N-3 methyl substitution, 2.41 in xanthines with N-1 and/or N-7 methyl substitution and 1.68 in xanthines with N-9 methyl substitution.