Pharmacokinetics and metabolism of codeine in humans

Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine‐6‐glucuronide 81·0 ± 9·3 per cent, norcodeine 2·16 ± 1·44 per cent, morphine 0·56 ± 0·39 per cent, morphine‐3‐glucuronide 2·10 ± 1·24 per cent, morphine‐6‐glucuronide 0·80 ± 0·63 per cent, and normorphine 2·44 ± 2·42 per cent. Two out of eight volunteers were unable to O ‐dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half‐life of codeine was 1·47 ± 0·32 h, that of codeine‐6‐glucuronide 2·75 ± 0·79 h, and that of morphine‐3‐glucuronide 1·71 ± 0·51 h. The systemic clearance of codeine was 2280 ± 840 ml min −1 , the renal clearance of codeine was 93·8 ± 29·8 ml min −1 , and that of codeine‐6‐glucuronide was 122 ± 39·2 ml min −1 . The plasma AUC of codeine‐6‐glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine‐6‐glucuronide in vivo was 56·1 ± 2·5 per cent and 34·0 ± 3·6 per cent, respectively. The in vitro protein binding of norcodeine was 23·5 ± 2·9 per cent; of morphine, 46·5 ± 2·4 per cent; of normorphine, 23·5 ± 3·5 per cent; of morphine‐3‐glucuronide, 27·0 · 0·8 per cent; and of morphine‐6‐glucuronide, 36·7 ± 3·8 per cent.