The Metabolism of Benzodioxane Derivatives. II. Ethoxybutamoxane-C<sup>14</sup>

McMahon, Robert E.; Welles, John S.; Lee, Henry M.

doi:10.1021/ja01496a047

Cited by 14 publications

(6 citation statements)

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“…M2 is a major metabolite and is formed by N‐dealkylation on the other side of the nitrogen with further oxidation to an acid, a well‐established metabolic pathway 27. M2 is weakly detected in +ESI with much of the ion current being associated with adduct species.…”

Section: Resultsmentioning

confidence: 99%

Application of polarity switching in the identification of the metabolites of RO9237

Fitch

et al. 2007

Rapid Comm Mass Spectrometry

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Polarity switching mass spectrometry is an efficient way to collect structural data on drug metabolites. The value of this approach is illustrated with the in vitro metabolism of RO9237. Metabolites are identified by positive and negative electrospray ionization (ESI) full scan mass spectrometry, MS/MS and MS(3) using unlabelled and (14)C-radiolabelled versions of the drug. Comparison of the relative detectability of these metabolites by +ESI and -ESI shows that neither ESI mode is universal. It is advantageous to screen for metabolites using both positive and negative ionization modes. This is especially true for phase II metabolism which tends to make molecules more polar and often more acidic. Identification of phase II metabolites also benefits greatly from MS(3) experiments because the conjugating groups typically are cleaved in MS/MS and information on the core structure is only obtained in MS(3). A special case of phase II metabolism is the generation of glutathione (GSH) conjugates from reactive metabolites. The detection of GSH conjugates also benefits from generating both positive and negative ESI mass spectral data.

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Section: Resultsmentioning

confidence: 99%

Application of polarity switching in the identification of the metabolites of RO9237

Fitch

et al. 2007

Rapid Comm Mass Spectrometry

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“…These were derived from m-or p-amino-9-phenylguanine attached to benzenesulfonyl fluoride by a sulfonamide, carboxamide, or urea bridge. Three excellent irreversible inhibitors emerged that at a concentration of 10~6 to 10~7 M gave total inactivation of xanthine oxidase with a half-life of 1 min or less; these were 9-phenylguanines substituted by a p-(p-fluorosulfonylbenzamido) (2), p-(wi-fluorosulfonylbenzamido) (7), or m-(p-fluorosulfonylbenzenesulfonamido) (21) moiety. 9-Phenylguanine (1) is a good reversible inhibitor of 2, R= p-NHC0C6H4S02F-p 3, R = ra-NHC0C6H4S02F-p 4, R = m-NHC0C6H4S02F-m 5, R = m-NHC0NHC6H4S02F-m 6, R= p-0(CH2)"NH~S02F-m xanthine oxidase4,5 with the 9-phenyl group interacting with the enzyme by hydrophobic bonding.…”

Section: Resultsmentioning

confidence: 99%

“…Twenty-four hours following the last injection of stimulatory agent, the rate of demethylation in vivo was assayed by radiorespirometry as described above. One control group, one compound 1 group (6-day treatment), and one phenobarbital group were tested with butynamine-N-methyl-lJC (7 mg/kg, 1.5 juCi) as substrate. In a second experiment a control group, a compound 1 group (12-day treatment), and a phenobarbital group were tested with diphenamid-N-methyl-1 'C (50 mg/kg) as substrate.…”

Section: Methodsmentioning

confidence: 99%

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Demethylation studies. VI. Inhibition of hepatic microsomal oxygenation by .beta.-(2,4-dichloro-6-phenylphenoxy)ethylamine and related compounds

McMahon¹,

Mills²,

Culp³

et al. 1969

J. Med. Chem.

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“…Benzodio%anes.-Marked species differences have been observed in the metabolism of a series of benzodioxane central nervous system depressants (103)(104)(105). Butamoxane, 2-butylaminomethyl-I, 4-benzodioxane, was meta bolized in both the rat and dog through ring hydroxylation at the 6-or 7-position.…”

Section: A-heterocyclicsmentioning

confidence: 99%

Species Differences in Drug Metabolism

Hücker¹

1970

Annu. Rev. Pharmacol.

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INTRODUcrIONThe importance of species differences in drug metabolism in understand ing the mechanism of action of many drugs has become increasingly evi dent. Several reviews and articles on the overall topic of drug metabolism have covered aspects of it (1-17). In addition, discussion of species differ ences in drug metabolism formed an important segment of a recent sympo sium, the proceedings of which contain a number of very informative papers (18)(19)(20)(21)(22)(23)(24).It would appear that the increasing interest in the subject stems from the premise that improved understanding and broader knowledge of species differences in drug metabolism will greatly improve our abilities to predict the pharmacologic and toxic010gic properties of a given compound in man from experimental data obtained in animals. It should also be pointed out that such studies, even when only indirectly reIated to drug therapy, have yielded valuable new biochemical information of quite fundamental nature. Examples of this type concern acetyl CoA, the role of pyridine nucleotides in oxygen incorporation, mechanisms of enzyme adaptation, human genetics, phylogenetic and ontogenetic enzyme development, intracellular structure, organ and membrane function, and biosynthesis of vitamin C (25). The in creased interest is also probably correlated with recent technological adv ances that will possibly enable one to study the physiological disposition and metabolic fate of a compound in several species within a relatively short pe riod of time.If the above comments sound encouraging, they may also be unduly opti mistic, at least insofar as prediction is concerned. For example, Williams (19) stated that aromatic hydroxylation varies quantitatively and qualita tively in haphazard fashion among species, and that one can not, at present, draw definite conclusions about the relationship between drugs, species, and metabolic routes. Brodie (23) is equally discouraging in another sense, namely, the possibility of discovering an animal species, that, drug-metabo lism-wise, is greatly similar to man. It should be pointed out here, however, that very little work of this type has been done with the higher nonhuman primates, i.e., the chimpanzee, gorilla, and orang-utan. The reader should also beware of the catchall name "monkey"since in many papers it refers to 99 Annu. Rev. Pharmacol. 1970.10:99-118. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/14/15. For personal use only.Quick links to online content Further ANNUAL REVIEWS

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The Metabolism of Benzodioxane Derivatives. II. Ethoxybutamoxane-C¹⁴

Cited by 14 publications

References 1 publication

Application of polarity switching in the identification of the metabolites of RO9237

Application of polarity switching in the identification of the metabolites of RO9237

Demethylation studies. VI. Inhibition of hepatic microsomal oxygenation by .beta.-(2,4-dichloro-6-phenylphenoxy)ethylamine and related compounds

Species Differences in Drug Metabolism

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The Metabolism of Benzodioxane Derivatives. II. Ethoxybutamoxane-C14

Cited by 14 publications

References 1 publication

Application of polarity switching in the identification of the metabolites of RO9237

Application of polarity switching in the identification of the metabolites of RO9237

Demethylation studies. VI. Inhibition of hepatic microsomal oxygenation by .beta.-(2,4-dichloro-6-phenylphenoxy)ethylamine and related compounds

Species Differences in Drug Metabolism

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The Metabolism of Benzodioxane Derivatives. II. Ethoxybutamoxane-C¹⁴