Page 92 - Advances in Forensic Applications of Mass Spectrometry - Jehuda Yinon

1522_C02.fm Page 79 Wednesday, November 12, 2003 9:36 AM

Ketobemidone is a synthetic opioid agonist and narcotic analgesic which
is frequently abused, particularly in Scandinavian countries. Breindahl et
al. developed an LC/ESI/MS method for the determination of ketobemi-
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done and its demethylated metabolite in urine. Mixed-bed SPE cartridges
were used for isolation with a recovery of over 90%. Protonated quasi-
molecular ions for both substances as well as three fragments for ketobemi-
done were monitored. The LOD was 25 mg/l. Sunstrom et al. applied
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ESI/MS/MS for determination of ketobemidone, and its five phase I metab-
olites, as well as glucuronides of ketobemidone and norketobemidone in
human urine. The same group used ESI/qTOF/MS besides LC/MS/MS for
the determination of the glucuronides of ketobemidone, nor-, and
hydroxymethoxyketobemidone in urine. 59 The accuracy of the mass mea-
surement was better than 2 ppm.
The enantiomers of tramadol and its active metabolite O-desmethyltra-
madol were determined with LC/APCI/MS-MS. The substances were iso-
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lated from plasma with automated SPE and separated on a Chiralpak AD
column in isohexane–ethanol–diethylamine (97:3:0.1) mobile phase. The
transitions of protonated quasi-molecular ions of drugs and internal standard
(ethyltramadol) to the same ion m/z 58 were monitored. Also, other tramadol
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metabolites could be detected. Juzwin et al. determined tramadol N-oxide
and its major metabolites in the plasma of experimental animals, using
LC/ESI/MS/MS. The LOQ was 6 mg/l and the method was applied for pre-
clinical studies.
Methadone is a synthetic opioid of very long elimination half-life (15 to
55 h) which is used mainly as a heroin substitute in the treatment of heroin
addicts. Methadone is metabolized to inactive 2-ethylidene-1,5-dimethyl-
3,3-diphenylpyrrolidine (EDDP) and, to a lesser extent, to 2-ethyl-5-methyl-
3,3-diphenyl-1-pyrroline (EMDP). All these compounds contain a chiral
center, and the enantiomers could be separated. This is of pharmacological
relevance since (R)-(–)-methadone (levomethadone) is 25 to 50 times more
potent than the (S)-(+)-methadone. Commercial methadone preparations
may contain the racemic form or levomethadone. Kintz et al. published the
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first ESI/LC/MS method for enantioselective separation of methadone and
EDDP in hair, using deuterated analogs of all compounds for quantitation.
The results showed that the (R)-(–)-methadone is preferably deposited in
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human hair. Ortelli et al. applied LC/MS for enantioselective determination
of methadone in saliva and serum. The method was applied for the analysis
of samples taken from heroin addicts participating in methadone mainte-
nance program. Disposition of methadone after nasal, intravenous, and oral
application to volunteers was measured by LC/MS. The parent drug and
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EDDP were measured in blood, showing high bioavailability of methadone
by the nasal route.

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