Demethylated metabolites

Figure 5.47 Fragmentations pathways for (a) non-demethylated, and (b) demethylated metabolites of Bosentan. Reprinted by permission of Elsevier Science from Exact mass measurement of product ions for the structural elucidation of drug metabolites with a tandem quadrupole orthogonal-acceleration time-of-flight mass spectrometer , by Hopf-gartner, G., Chernushevich, I. V., Covey, T., Plomley, J. B. and Bonner, R., Journal of the American Society for Mass Spectrometry, Vol. 10, pp. 1305-1314, Copyright 1999 by the American Society for Mass Spectrometry.

Amoxapine is a demethylated metabolite of loxapine and, as a result of its postsynaptic receptor DA-blocking effects, may be associated with extra-pyramidal side effects. 

Our next examples concern ring-substituted succinimides. 2-Phenylsuc-cinimide (4.185), the A-demethylated metabolite of the antiepileptic drug phensuximide, was found to be a better substrate of DHPase than succinimide itself. Two ring-opened metabolites are conceivable, 3-phenylsuccin-amic acid (4.186) and 2-phenylsuccinamic acid (4.187), but only the latter was formed enzymatically. 2-Phenylsuccinimide is chiral, and ring-opening... 

The parent drug phensuximide (4.188) was not enzymatically cleaved, suggesting that Af-alkylation abolishes enzymatic ring opening. Furthermore, no ring-opened metabolites of methsuximide (4.189) were detected. In this case, however, disubstitution of C(2) rather than Afalkylation prevented hydrolysis, since 2-methyl-2-phenylsuccinimide (4.190), its TV-demethylated metabolite, was not a substrate of DHPase [119]. 

V-Subslilulion and 5,5-disubstitution prevent ring opening as demonstrated by various examples. Ethotoin (3-ethyl-5-phenylhydantoin, 4.230), in contrast to its /V-dcclhylalcd metabolite, was not detectably hydrolyzed by DHPase. No ring-opened metabolite was found for phenytoin (5,5-diphenyl-hydantoin, 4.231) or nirvanol (5-ethyl-5-phenylhydantoin, 4.232), which is the AT-demethylated metabolite of mephenytoin (4.233) [144],... 

G. Lhoest, R. K. Verbeeck, N. Maton, P. Muthelet, D. Latinne, The in vivo Immunosuppressive Activity of the C15-Demethylated Metabolite of FK-506 Is Governed by Ring- and Open-Chain Tautomerism Effects , J. Pharmacol. Exp. Ther. 1995, 274, 622 -626. 

Kosel M, Eap CB, Amey M, Baumann P. 1998. Analysis of citalopram and its demethylated metabolites using chiral liquid chromatography. J Chromatogr B 719 234-238. 

Maris FA, Dingier E, Niehues S. 1999. High-performance liquid chromatographic assay with fluorescence detection for the routine monitoring of the antidepressant mirtazapine and its demethyl metabolite in human plasma. J Chromatogr B Biomed Sci Appl 721(2) 309-316. 

Shams M, Hiemke C, Hartter S. 2004. Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum. Ther Drug Monit 26(1) 78-84. 

Weigmann H, Hartter S, Maehrlein S, Kiefer W, Kramer G, et al. 2001. Simultaneous determination of olanzapine, clozapine and demethylated metabolites in serum by on-line column-switching high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 759(1) 63-71. 

Huang LF, Guo FQ, Liang YZ, Li BY, Cheng BM. 2004. Simultaneous determination of L-arginine and its mono-and demethylated metabolites in human plasma by high-performance liquid chromatography-mass spectrometry. Anal Bioanal Chem 380 643. 

Fig. 1.19 (A) Q1 full-scan spectrum of bosentan [(M-l-H), m/z 552], its demethylated metabolite [(M-l-H), m/z 538] and its hydroxylated metabolite [(M- -H), m/z 568], (B) product ion spectrum of bosentan, (C) precursor ion spectrum, (D) neutral loss spectrum. Electrospray ionization is in positive ion mode.

Pharmacokinetics Dextromethorphan is rapidly absorbed from the Gl tract. It undergoes metabolism in the liver and is then excreted in the urine as unchanged drug and demethylated metabolites. 

Diazepam, oxazepam, and N-desmethyldiazepam have been determined under isocratic conditions (342) a somewhat more sensitive assay for diazepam and N-methyldiazepam has been reported (545). The closely related compounds, chlordiazepoxide and its N-demethyl metabolite, have also been determined (344). Analysis of the antidepressant amitriptyline, its metabolites and related drugs have been carried out using a four-component solvent (345, 346) and also aqueous acetonitrile (547). 

Hexamethylmelamine is readily absorbed after oral administration, with peak plasma levels achieved after 1 hour. The drug is readily metabolized to form a number of demethylated metabolites. Urinary elimination is the primary route of drug excretion. 

A 10-year-old boy has a 4-month history of fears of contamination and of refnsing food becanse there might be monster drool in it. He is begnn on clomipramine (CMl), initially 25 mg at night, and the dosage is gradnally increased to three times daily. He complains of mild confusion and dry mouth. A trough blood level of CMl and its demethylated metabolite reveal that CMl is 455 ng/mL and desmethyl CMl is 48 ng/mL. 

Rochat, B., Amey, M., and Baumann, P. (1995a) Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit 17 273-279. 

Ronfeld, R.A., Tremaine, L.M., and Wilner, K.D. (1997) Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 32(Suppl 1) 22-30. 

It is dextro isomer of propoxyphene which is an analgesic and possesses antitussive property. It has low analgesic activity even half of codeine. It is metabolized in Uver. Side effects include vomiting, epigastric distress and sedation. The demethylated metabolite of propoxyphene is cardiotoxic. It is used in the treatment of mild type of pain. 

Among FICAs, clomipramine is one of the more selective reuptake inhibitors of serotonin. Because plasma levels of its demethylated metabolite (which primarily works through the NE system) can in some patients exceed those of the parent compound, its therapeutic action cannot be solely attributed to serotonin uptake inhibition. 

Because of these two separate and largely inaccessible chiral centers there are, in theory, four distinct isomers of ibogaine which are difficult to resolve. When the term "synthetic" is used in regard to ibogaine in the scientific journals, it usually applies to the resynthesis of the parent alkaloid from the demethylated metabolite. For reference purposes, here are the finger print number from the infrared spectra For the free base IR (in cm-1) 741, 799, 830, 1037, 1111, 1148 mp 152-153 °C. For the hydrochloride salt IR (in cm-1) 638, 810, 832, 925, 1031, 1149 mp 299-300 °C (dec). 

Residues of methylene blue in edible animal tissues are of public health concern because tliis dye and its metabolites are mutagenic (74). Metabolism studies in cattle have indicated that methylene blue can be eliminated in urine partly unchanged, partly metabolized to leucomethylene blue, or demethylated to N-methyl homologues of thionin, the completely demethylated metabolite of methylene blue, or reduced in vivo and subsequently eliminated in its leuco-form or in one or more chromogenic substances (75). 

Dextromethorphan and its O-demethylated metabolite dextrorphan (morphinans), are also low to medium affinity NMDA channel blockers. The former has been in clinical use as an antitussive for about 40 years and could therefore be considered as a very safe drug (Bern et al., 1992). 

Hydrocodone is a semisynthetic opioid derived from codeine.18It is utilized as an analgesic and antitussive available for oral administration, often in combination with acetaminophen or ibuprofen. As a rule, potent analgesics containing a methoxyl group at position 3 (e.g., hydrocodone, K, = 19.8 nM) bind the mu receptor relatively weakly, but their O-demethylated metabolites (such as hydromorphone, Kt = 0.6 nM) bind more strangely. As with oxycodone, the possibility exists that some of their ability to relieve pain may actually derive from their active metabolites 48... 

Accumulation of a demethylated metabolite of meperidine, normeperidine, may occur in patients with decreased renal function or those receiving multiple high doses of the drug. In sufficiently high concentrations, normeperidine may cause seizures. 

The same phenomenon was observed for mitraciliatine (10) and the closed ring E alkaloids 14-19, where the percentage metabolism by O-demethylation estimated by formaldehyde production ( 1%) was much less than the degree of total metabolism (25-69%). Nevertheless, both hirsutine and mitraciliatine gave detectable amounts of a compound assumed by TLC analysis to be an 0-(17)-demethyl metabolite, whereas such was not the case with 14-19. Hirsutine and mitraciliatine were also metabolized (to unidentified products) by both rat and guinea pig liver microsomes, which did not metabolize alkaloids 4-6, 9, and 11-13. 

Chen et al. used MeOH for precipitation of rat plasma in a 3 1 volume ratio to investigate a broad spectrum of biotransformation products generated from ani-sodine [5], anisodamine [6], atropine [52] and scopolamine [87], Biotransformation products covered a broad spectrum of polarity including sulfo- and glucuronide conjugates, oxidized, hydroxylated, methoxylated and demethylated metabolites of the parent drug as well as its hydrolysis products. Unfortunately, recoveries were not reported (Table 2). 

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