BIOTRANSFORMATION AND PHARMACOKINETICS OF ETHYLMORPHINE AFTER A SINGLE ORAL DOSE

1 The pharmacokinetics of ethylmorphine after administration of a sing le dose of the cough mixture Cosylan(R) were investigated in 10 health y subjects. 2 The median urinary recovery of ethylmorphine and measure d metabolites was 77% over 48 h. The median t(max) of unchanged ethylm orphine was 45 min, and the terminal elimination t(1/2) was 2 h. Ethyl morphine-6-glucuronide was found to be the major metabolite. 3 Two sub jects had significantly lower urinary recovery (0,48 h) of morphine an d morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MR(0)) and partial metabolic clearances (CL (m0)) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine typ e. 4 Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five ho mozygote (wt/wt) and five heterozygote subjects. Two subjects phenotyp ically classified as poor metabolisers were genotypically CYP2D6A/wt a nd CYP2D6D/wt, respectively. 5 Serum and urine samples taken more than 8 and 24 h after administration of ethylmorphine respectively, contai ned morphine and morphine-glucuronides, but no ethylmorphine, ethylmor phine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6 -glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6 The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Cons titutional variation in other enzymatic pathways involved in ethylmorp hine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administra tion of ethylmorphine. Norethylmorphine should be included in urine as says for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained m ore than 24 h after drug administration.