Biotransformation of mianserin in laboratory animals and man

Abstract

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.

Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004

“…The ions at m/z 315, 299, 298, and 240 for 4 and 299, 298, 256, and 240 for 3 correspond to the loss of a glucuronic acid moiety (m/z 315), loss of a glucuronic acid moiety and oxygen (m/z 299), and loss of an O-glucuronic acid moiety and fragmentation of the piperazine ring (m/z 240 and 256). This pattern is consistent with the fragmentation of glucuronic acid conjugate metabolites of a monooxygenated piperazine derivative (Delbressine et al, 1992;Schaber et al, 2001;Miller et al, 2004). Analysis of the (bio)synthesized standards containing 3 and 4 using MicrOTOF MS showed the compounds to have exact mass values of 491.18608 and 491.18325, respectively.…”

“…The exact mass data obtained for 3 and 4 (corresponding to C 24 H 31 N 2 O 7 S), and their fragmentation patterns are consistent with monooxygenated glucuronide metabolites of the piperazine 1 (Delbressine et al, 1992;Schaber et al, 2001;and Miller et al, 2004).…”

“…Chemical shifts and coupling constants of tertiary N-glucuronides and ␤-anomers are found at 5.33 to 6.31 ppm and 8.3 to 9.5 Hz, respectively (Andersen et al, 1989;Keating et al, 2006;Nakazawa et al, 2006;Yan et al, 2006), which are at lower field (higher parts per million) than the anomeric proton of N-O-glucuronides (range of chemical shift 4.54 -4.84 ppm and coupling constants of 8.4 -9 Hz) (Straub et al, 1988;Delbressine et al, 1992;Turgeon et al, 1992;Schaber et al, 2001;and Miller et al, 2004). The N-Oglucuronide 3 fits the published range.…”

“…Drugs that are piperazine derivatives typically generate piperazine ring carbon alcohols or metabolize at the piperazine nitrogen to generate hydroxylamines/N-oxides as phase I metabolites and Nglucuronides or N-O-glucuronides as phase II metabolites (Delbressine et al, 1992;Kassahun et al, 1996;Schaber et al, 2001;Miller et al, 2004). N-Glucuronides are common metabolic products of drugs containing amino groups or aromatic nitrogen heterocycles and in some cases tertiary, secondary, and primary amines form N-glucuronides from a drug and its phase I metabolites (Dalgaard and Larsen, 1999).…”

Species Differences in the Biotransformation of an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

“…However, because of the significance of M5 in monkeys reported herein, LC/MS/NMR analyses of nonradiolabeled M5 purified from the urine of a monkey administered 1 unequivocally identified M5 as an N-O-glucuronide of 1, consistent with the mechanistic structural rationalization of fragment ions within its product ion spectrum (Fig. 3) and previously characterized alicyclic N-O-glucuronides (Straub et al, 1988;Delbressine et al, 1992;Edlund and Baranczewski, 2004;Miller et al, 2004). In particular, the 1 H spectrum of M5 clearly showed the anomeric proton signal (4.37 ppm) of the glucuronide moiety, whereas the correlation spectroscopy spectrum indicated that this was the most downfield resonance in a five-proton spin system that terminated with a doublet at 3.59 ppm.…”