Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

Abstract

1 The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan® were investigated in 10 healthy subjects. 2 The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t'/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3 Two subjects had significantly lower urinary recovery (0,48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmo) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4 Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5 Serum and urine samples taken more than 8 and 24 h after administration of ethylmorphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-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. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration.

The detection of dihydrocodeine and its main metabolites in cases of fatal overdose

“…The prevalence of poor metabolizers in a group of healthy Caucasians was expected to be 7-10% [8]. CYP2D6 also catalyses dealkylation of the opioids codeine [3,21,22], hydrocodone, oxycodone [10] and ethylmorphine [1].…”

Opioids: 3.4 Opioids with Clinical Relevance

“…Pharmacokinetic properties: Ethylmorphine (Aasmundstad et al, 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O-and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides.…”

Synthesis, characterization, method development, and validation of nor‐ethylmorphine hydrochloride reference material using established analytical techniques for dope control analysis

“…Ethylmorphine is the 3‐ethoxy homolog of morphine, which is being used as an analgesic and antitussive agent for therapeutic purposes 1 . Ethylmorphine is permitted internationally for therapeutic purposes where morphine is not approved or indicated across the globe 2,3 . In contrast to morphine, ethylmorphine is permitted for oral intake by athletes, 4 and it is metabolized to morphine (via O ‐deethylation) and nor‐ethylmorphine via N ‐demethylation, which are both excreted into the urine 5 .…”