Norcodeine

Abstract: 1. A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3- and 6-glucuronides (M3G and M6G) + normorphine], N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM]) and glucuronidation (codeine/codeine-6-glucuronide (C6G] were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2. There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (rs = 0.77, P less than 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3. The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4. The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5. No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6. The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.

Abstract: 1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)