PubMed · 7261114
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J Korpás, G Nosál'ová. 1981. [Tussiphonography].. https://pubmed.ncbi.nlm.nih.gov/7261114/
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OBJECTIVE: The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 respectively. The formation rates of morphine by O-demethylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes. RESULTS: Relatively high K(m) values were found for both O- and N-demethylations, suggesting a low affinity to the corresponding enzymes. The inhibitory effects of various drugs were found to be different for O- and N-demethylations. The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol inhibited the O-demethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong inhibitors of the N-demethylation of codeine. Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A. Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent. CONCLUSION: It seems that there was a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen for drugs which interact with these two important drug-metabolising enzymes.
Following enzymatic hydrolysis of urine, a gas chromatography-mass spectrometry method for the simultaneous determination of codeine, morphine, hydrocodone, and hydromorphone uses hydroxylamine to form oxime derivatives of the keto-opiates (i.e., hydrocodone, hydromorphone, oxycodone, and oxymorphone). These trimethylsilyl-derivatized forms no longer interfere with the detection and quantitation of codeine and morphine. Samples are extracted on solid-phase columns and quantitated by deuterated internal calibrations of each analyte with selected ion monitoring. Codeine, morphine, hydrocodone, and hydromorphone are completely separated, allowing simultaneous quantitation without interference and a chromatographic analysis time < 9 min.
There has been much debate in urine drug testing over what criteria should be applied to total codeine and total morphine concentration data to determine the likelihood that a urine donor has used heroin and whether such use can be demonstrated by the presence of 6-acetylmorphine. After determining that the stability of 6-acetylmorphine in frozen urine is adequate for a period of at least two years, a database of over 100 codeine and/or morphine positive urine specimens was subjected to relative operating characteristic analysis to identify a criterion that would indicate a high probability of detecting 6-acetylmorphine in a specimen and thus confirming heroin use. A two-fold criterion was identified. By using a criterion that requires the total morphine concentration to be greater than 5.000 mg/L and the total codeine to total morphine ratio to be less than 0.125, one can predict the presence of 6-acetylmorphine with a sensitivity of 92%, a specificity of 79%, and an overall accuracy of 73%. Although this criterion is statistically the most accurate in terms of both sensitivity and specificity for the data analyzed by the author, the results of other, criteria are presented to aid toxicologists and medical review officers in determining if analysis for 6-acetylmorphine is likely to produce useful results.