Ta. Aasmundstad et al., BIOTRANSFORMATION AND PHARMACOKINETICS OF ETHYLMORPHINE AFTER A SINGLE ORAL DOSE, British journal of clinical pharmacology, 39(6), 1995, pp. 611-620
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.