Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.
1. The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate. 2. The total 8 h urinary recovery of drug-related material was 74 +/- 24% in the Caucasians and 60 +/- 14% in the Chinese (P less than 0.001). The excretion of unchanged codeine was significantly higher in the Chinese (7.2%) compared with the Caucasians (4.3%, P less than 0.001). 3. The Caucasians excreted significantly greater proportions of codeine-6-glucuronide (C6G) (62%) than the Chinese (44%) (P less than 0.001). The frequency distribution of the log metabolic ratio (MR) for glucuronidation (codeine/C6G) was shifted towards higher values in the Chinese population. Males in both groups and Chinese smokers had significantly lower glucuronidation MRs than females and non-smokers in the respective populations (P less than 0.001). 4. The frequency distribution of the MR for O-demethylation (codeine/morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM) was highly skewed in the Caucasians, suggestive of a bimodal distribution. There was a 160-fold interindividual variation in this MR. A unimodal distribution of the log O-demethylation MR was observed in Chinese. The Caucasians excreted less M and more M6G than did the Chinese (P less than 0.001). 5. Significantly more norcodeine (NC) and less NC-glucuronide (NCG) were excreted in the Chinese compared with the Caucasians (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Yue
Q Y
QY
Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.
Svensson
J O
JO
Alm
C
C
Sjöqvist
F
F
Säwe
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People; D003061:Codeine / Q000378:metabolism*; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D003640:Dealkylation; D005006:Ethnicity; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D007206:Individuality; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D012907:Smoking / Q000378:metabolism; D044465:White People
D003278:Contraceptives, Oral, Hormonal; D005965:Glucuronates; D003061:Codeine