Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.

Abstract

1 The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2 The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 ± 340 nmol 1-1 h, 2.58 ± 0.57 h and 2.02 ± 0.73 1 h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3 PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P < 0.0001), and lower partial metabolic clearance by O-demethylation (P < 0.0001). In contrast, the PM had higher AUC of NC (P < 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4 Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N-and O-demethylations, respectively. 5 The total recovery of drug-related material in 48 h urine collections ranged from 71% to 106% of the dose and did not differ between EM and PM. Six percent of the dose was O-demethylated in EM and the majority of the metabolites produced through this pathway were conjugated. Unconjugated M accounted for less than 0.2% of the dose. In PM, only 0.33% of the dose was metabolized by O-demethylation and M was negligible (0.001% of the dose). However, PM had a significantly higher recovery of NC (P < 0.001) than EM. There was no significant difference between EM and PM in the recovery of codeine, C6G and NCG, and in the renal clearance of codeine or any of its metabolites. 6 Data from a chronic dosing study including three EM and three PM confirmed the results of the single dose study. 7 The clinically important findings were the negligible plasma concentration of the 0-demethylated active metabolites M6G, NM and M in PM, and the relatively high concentrations of M6G and NM in EM. Considering the low plasma concentration of M as well as the potent analgesic effects of M6G and NM, the latter compounds might play an important role in the analgesic effect of codeine.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…In most individuals only a small fraction (ϳ10%) of codeine is metabolized to morphine via CYP2D6 (Caraco et al, 1996), with most being glucuronidated to codeine-6-glucuronide and the remainder being metabolized by CYP3A4 to norcodeine . The AUC of codeine is similar in PMs and in EMs (Yue et al, 1991;Mikus et al, 1997;Eckhardt et al, 1998), whereas morphine is virtually undetectable in PMs (Yue et al, 1991;Caraco et al, 1996;Poulsen et al, 1996b;Eckhardt et al, 1998), as well as in EMs taking quinidine (phenocopying) (Desmeules et al, 1991;Sindrup et al, 1992a;Caraco et al, 1996). Clinical studies in volunteers generally support the lack of analgesia in PMs, which is consistent with the belief that morphine is the key metabolite responsible for the antinociceptive effects of codeine (Desmeules et al, 1991;Sindrup et al, 1991;Poulsen et al, 1996b;Eckhardt et al, 1998).…”

In Vitro–In Vivo Extrapolation Predicts Drug–Drug Interactions Arising from Inhibition of Codeine Glucuronidation by Dextropropoxyphene, Fluconazole, Ketoconazole, and Methadone in Humans

“…where [I] is the inhibitor concentration; f m is the fraction of COD hepatic clearance via glucuronidation (taken here as 80%; Yue et al, 1991), and K i is the inhibition constant generated in vitro. The inhibitor concentration ([I]) was taken as the maximum hepatic maximum inlet concentration of the drug in vivo (Miners et al, 2010);…”

“…Other elimination pathways include glucuronidation, N-demethylation, and renal clearance of unchanged drug. Of these, glucuronidation, to form COD-6-glucuronide (C6G), is the dominant metabolic pathway, accounting for 80 to 85% of the COD dose recovered in urine (Yue et al, 1991).…”

“…It is generally accepted that COD analgesia arises from CYP2D6 catalyzed O-demethylation to form morphine (Somogyi et al, 2007). Approximately 4 to 10% of a COD dose is converted to morphine in CYP2D6-extensive metabolizers (Chen et al, 1991;Yue et al, 1991). Other elimination pathways include glucuronidation, N-demethylation, and renal clearance of unchanged drug.…”

Pharmacological Management of Cancer-Related Pain

“…A total of 10% of codeine is broken down to morphine by CYP2D6, an enzyme lacking in 5% to 10% of white populations. 44 Codeine use is not recommended in the setting of renal failure. 45 One placebo-controlled study has evaluated codeine for cancer pain involving a sustained-release formulation.…”