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Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine
1Department of Clinical Pharmacology, Huddinge University Hospital, Karolinska Institute, Sweden.
Aims:
To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O-demethylation were also compared for their ability to determine phenotype.
Methods:
Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O-demethylation, N-demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects.
Results:
In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O-demethylation (codeine/(morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM)). Admixture analysis confirmed the co-segregation of codeine O-demethylation and debrisoquine hydroxylation. The antimode for the codeine O-demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O-demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N-demethylation, O-demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots.
Conclusion:
A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O-demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.