DISPOSITION AND METABOLISM OF CODEINE AFTER SINGLE AND CHRONIC DOSES IN ONE POOR AND 7 EXTENSIVE METABOLIZERS

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 metabolisher of dextromethorphan). Codeine, codeine-6-glucoronide, 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 > 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 metabolishers and 8 ml min-1 in the poor metabolisher; 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 > 0.05) altered by chronic administration. In the seven extensive metabolishers the values of partial clearance to morphine were not significantly (P > 0.05) different from those to norcodeine. 7 The usefulness of measuring partial clearances was illustrated by the detection of the poor oxidative metabolisher to morphine, whereas the measurement of parent compound in plasma did not identify this important metabolic defect. 8 Poor metabolishers of codeine may not derive any of the pharmacological effects associated with codeine.