Metabolism of methapyrilene by Fischer-344 rat and B6C3F1 mouse hepatocytes.

1. Suspension cultures of freshly isolated F344 rat and B6C3F1 mouse hepatocytes were compared for their ability to transform various concentrations of methapyrilene (MP). 2. MP metabolites were isolated and purified by h.p.l.c., and were identified by comparing their chromatographic and mass spectral properties with those of authentic standards. 3. Both rat and mouse hepatocytes transformed MP to tentatively identified 2-thiophenecarboxylic acid (I), and definitively identified mono-N-desmethyl methapyrilene glucuronide (II), methapyrilene glucuronide (III), methapyrilene N-oxide (V), and mono-N-desmethyl methapyrilene (VII).

[1]  W. Lijinsky.  Chronic toxicity tests of pyrilamine maleate and methapyrilene hydrochloride in F344 rats. , 1984, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[2]  W. Lijinsky,et al.  Failure of methapyrilene to induce tumors in hamsters or guinea pigs. , 1983, Journal of toxicology and environmental health.

[3]  W. Slikker,et al.  The metabolism and elimination of pyrilamine maleate in the rat. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[4]  J. Spalding,et al.  Examination of genotoxicity, toxicity and morphologic alterations in hepatocytes following in vivo or in vitro exposure to methapyrilene. , 1988, Carcinogenesis.

[5]  S. Lawrence,et al.  DNA damage induced by the antihistaminic drug methapyrilene hydrochloride. , 1982, Mutation research.

[6]  D. Schmitz,et al.  The in vivo metabolism of methapyrilene, a hepatocarcinogen, in the rat. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[7]  J. Lay,et al.  Characterization of seven antihistamines, their N-oxides and related metabolites by fast atom bombardment mass spectrometry and fast atom bombardment tandem mass spectrometry. , 1989, Biomedical & environmental mass spectrometry.

[8]  H. Pitot,et al.  Effect of the antihistamine, methapyrilene, as an initiator of hepatocarcinogenesis in female rats. , 1989, Cancer letters.

[9]  L. M. Brennan,et al.  The effects of methapyrilene hydrochloride on hepatocarcinogenicity and pentobarbital-induced sleeping time in rats and mice. , 1982, Toxicology and applied pharmacology.

[10]  N. Castagnoli,et al.  Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of methapyrilene. , 1981, Journal of medicinal chemistry.

[11]  D. Clive,et al.  Methapyrilene is a genotoxic carcinogen: studies on methapyrilene and pyrilamine in the L5178Y/TK +/- mouse lymphoma assay. , 1987, Mutation research.

[12]  J. Shaddock,et al.  The potent hepatocarcinogen methapyrilene does not form DNA adducts in livers of Fischer 344 rats. , 1988, Mutation research.

[13]  D. Casciano,et al.  The isolation and primary culture of viable, nonproliferating rat hepatocytes , 1979 .

[14]  Walter A. Korfmacher,et al.  Fast-atom bombardment and thermospray mass spectrometry for the characterization of two glucuronide metabolites of methapyrilene. , 1989, Rapid communications in mass spectrometry : RCM.

[15]  W. Lijinsky,et al.  A comparison of in vivo and in vitro metabolites of the H1-antagonist N,N-dimethyl-N'-2-pyridyl-N'-(2-thienylmethyl)-1,2-ethanediamine (methapyrilene) in the rat. , 1987, Xenobiotica; the fate of foreign compounds in biological systems.

[16]  Walter A. Korfmacher,et al.  Fungal transformations of antihistamines: metabolism of methapyrilene, thenyldiamine and tripelennamine to N-oxide and N-demethylated derivatives. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  G. Probst,et al.  An evaluation of the L5178Y TK+/- mouse lymphoma forward mutation assay using 42 chemicals. , 1984, Mutation research.

[18]  B. E. Stewart,et al.  Chromosome analysis of trifluorothymidine-resistant L5178Y mouse lymphoma cell colonies. , 1986, Environmental mutagenesis.

[19]  Walter A. Korfmacher,et al.  Desorption chemical ionization and fast atom bombardment mass spectrometric studies of the glucuronide metabolites of doxylamine. , 1986, Biomedical & environmental mass spectrometry.

[20]  G. Probst,et al.  The induction of unscheduled DNA synthesis by antihistamines in primary hepatocyte cultures. , 1980, Cancer letters.

[21]  D. Schmitz,et al.  Metabolism of methapyrilene by rat-liver homogenate. , 1986, Xenobiotica; the fate of foreign compounds in biological systems.

[22]  W. Lijinsky,et al.  Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride. , 1980, Science.

[23]  D. Casciano,et al.  Methapyrilene is inactive in the hepatocyte-mediated Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase mutational assay. , 1984, Cancer letters.

[24]  J. Shaddock,et al.  A study of the potential genotoxicity of methapyrilene and related antihistamines using the hepatocyte/DNA repair assay. , 1984, Mutation research.

[25]  Kammerer Rc,et al.  Species differences in the in vitro metabolism of methapyrilene. , 1987 .

[26]  J. Froines,et al.  Mutagenicity studies of selected antihistamines, their metabolites and products of nitrosation. , 1986, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[27]  G. Williams,et al.  Characterization of DNA repair elicited by carcinogens and drugs in the hepatocyte primary culture/DNA repair test. , 1981, Journal of toxicology and environmental health.