The in vivo metabolism of methapyrilene, a hepatocarcinogen, in the rat.
1. The metabolism of methapyrilene (I), was examined in vivo by g.l.c. and g.l.c.-mass spectrometric analysis of rat urinary extracts. 2. Dosing the animals with tetradeuterium-labelled I helped identify 7 different metabolites of I in the urine, including (5-hydroxylpyridyl)-methapyrilene, which was identified by comparison with a synthetic reference standard. 3. After 4 weeks of treatment with I, rats also excrete detectable amounts of the 3- and (6-hydroxylpyridyl)-methapyrilene metabolites suggesting that pretreatment with I alters the metabolism of the pyridine ring. 4. Metabolic removal of the 2-thienylmethylene moiety is also facile, as large amounts of N'-(2-pyridyl)-N,N-dimethylethylenediamine and its metabolite N'-[2(5-hydroxylpyridyl)]-N,N-dimethylethylenediamine are excreted under all dosing regimens. 5. Urinary concn of both I and metabolites decline with time, despite continuous dosing, indicating a change in absorption, metabolism, and/or excretion of I on repeated dosing.
Kammerer
R C
RC
Department of Pharmacology, UCLA School of Medicine 90024-1735.
Schmitz
D A
DA
Lampe
M A
MA
Kloc
K
K
D000631:Aminopyridines / Q000493:pharmacokinetics*; D000818:Animals; D003903:Deuterium; D008401:Gas Chromatography-Mass Spectrometry; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D008701:Methapyrilene / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains
D000631:Aminopyridines; D008701:Methapyrilene; D003903:Deuterium