Summary
The phenothiazine drug, levomepromazine (LM), is used in the treatment of psychiatric disorders and as an analgesic. A single 50 or 100 mg dose of LM was given to healthy male volunteers, and urine samples were collected for 24 h. The urine was treated with β-glucuronidase, purified by solid-phase extraction, and analyzed on a GC-MS system for identification of LM metabolites. Mass spectra suggesting 14 different LM metabolites were obtained from the samples. Out of these, 13 spectra could be ascribed to specific metabolites, 5 of which have not previously been identified. All these 5 metabolites were hydroxylated at the phenothiazine nucleus. Although the applied method did not determine the positions of hydroxyl groups on phenothiazine nuclei, 3 of the 5 metabolites were identified as O-desmethyl 3-hydroxy LM, O-desmethyl 7-hydroxy LM, and N,O-didesmethyl 7-hydroxy LM, based on their chromatographic properties. In addition two metabolites, one being hydroxylated on the phenothiazine nucleus, and one being O-demethylated and hydroxylated on the nucleus, were found. It is suggested that these were 8-hydroxy LM and O-desmethyl 8-hydroxy LM. The concentrations of 3-hydroxy LM (free+conjugated) appeared to be much higher than the concentrations of any other metabolite in the samples.
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Lippmann S.B. (1993): Can I use Levoprome (methotrimeprazine) in psychiatry? J. Clin. Psychopharmacol., 13, 456.
Johnsen H., Dahl S.G. (1982): Identification of O-demethylated and ring-hydroxylated metabolites of methotrimeprazine (levomepromazine) in man. Drug Metab. Dispos., 10, 63–67.
Bylund D.B. (1981): Interactions of neuroleptic metabolites with dopaminergic, alpha adrenergic and muscarinic cholinergic receptors. J. Pharmacol. Exp. Ther., 217, 81–86.
Dahl D.G., Hall H. (1981): Binding affinity of levomepromazine and two of its major metabolites to central dopamine and α-adrenergic receptors in the rat. Psychopharmacology, 74, 101–104.
Hals P.-A., Hall H., Dahl S.G. (1986): Phenothiazine drug metabolites: dopamine D2 receptor, α1- and α2-adrenoceptor binding. Eur. J. Pharmacol., 125, 373–381.
Hals P.-A., Hall H., Dahl S.G. (1988): Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. Life Sci., 43, 405–412.
Nowak J.Z., Arbilla S., Dahl S.G., Langer S.Z. (1990): Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites. Life Sci., 46, 443–451.
Dahl S.G., Refsum H. (1976): Effects of levomepromazine, chlopromazine and their sulfoxides on isolated rat atria. Eur. J. Pharmacol., 37, 241–248.
Passwal M., Dahl S.G., Refsum H. (1976): Anticholinergic and cardiodepressive effects of levomepromazine and two of its metabolites on isolated rat atria. Eur. J. Pharmacol., 40, 249–254.
Morel E., Lloyd K.G., Dahl S.G. (1987): Anti-apomorphine effects of phenothiazine drug metabolites. Psychopharmacology, 92, 68–72.
Hals P.-A., Dahl S.G. (1994): Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat. Pharmacol. Toxicol., 75, 255–260.
Davies D.S., Kahn G.C., Murray S., Brodie M.J., Boobis A.R. (1981): Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Biochem. Pharmacol., 11, 89–91.
Loennechen T., Andersen A., Hals P.-A., Dahl S.G. (1990): High-performance liquid chromatographic determination of levomepromazine (methotrimeprazine) and its main metabolites in serum and urine. Ther. Drug Monitor, 12, 574–581.
Sharples D. (1981): Photodecomposition of some substituted phenothiazines. J. Pharm. Pharmacol., 33, 242–243.
Dahl S.G., Garle M. (1977): Identification of nonpolar methotrimeprazine metabolites in plasma and urine by GLC-mass spectrometry. J. Pharm. Sci., 66, 190–193.
Dahl S.G., Johnsen H., Lee C.R. (1982): Gas chromatographic mass spectrometric identification of O-demethylated and mono-hydroxylated metabolites of levomepromazine in blood from psychiatric patients by selected ion recording with high resolution. Biomed. Mass Spectrom., 9, 534–538.
Dahl S.G., Kauffmann E., Mompon B., Purcell T. (1987): Nuclear magnetic resonance analysis of methotrimeprazine (levomepromazine) hydroxylation in humans. J. Pharm. Sci., 76, 541–544.
Turano P., Canton C., Turner W.J., Merlis S. (1968): Chromatographic evidence for the existence of 8-hydroxy-chlorpromazine in urine. Agressologie, 9, 193–194.
Alfredsson G., Lindberg M., Sedvall G. (1982). The presence of 7-hydroxychlorpromazine in CSF of chlorpromazine-treated patients. Psychopharmacology, 77, 376–378.
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Hals, P.A., Dahl, S.G. Metabolism of levomepromazine in man. Eur. J. Drug Metab. Pharmacokinet. 20, 61–71 (1995). https://doi.org/10.1007/BF03192290
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DOI: https://doi.org/10.1007/BF03192290