The biotransformation of nitrogen containing xenobiotics to lactams.

The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic metabolism lactams were identified as metabolites of nicotine, cyproheptadine, tremorine and prolintane. Now, because of the increasing availability of powerful analytical techniques, there are many instances of lactams being identified as metabolites. Lactam metabolites are formed from either iminium ions or carbinolamines. These two intermediates may have distinct mechanisms of formation but they can interconvert. There is evidence that the iminium ions are oxidized to lactams by aldehyde oxidases (cytosolic molybdenum hydroxylases). The tissue distribution and enzyme activities of aldehyde oxidase have been studied in several animal species. However, it is also known that iminium ions can undergo spontaneous hydrolysis to the corresponding carbinolamine. If the latter is stable it may undergo oxidation by cytochrome P-450 to form the lactam. Thus, species differences in lactam formation might be caused by differences in the concentrations of either cytochrome P450 isozymes or aldehyde oxidases. It appears that lactam formation is an end stage in the metabolism of N-heterocycles in that it is unlikely that the lactam will undergo hydrolysis to the corresponding amino acid. Such amino acids probably arise from the amino aldehydes that may be produced from ring opening of unstable carbinolamine intermediates. When microsomal preparations are incubated with the appropriate substrate in the presence of sodium cyanide the iminium ion may be trapped to produce a cyano compound. Such reactions have led to the proposal that iminium ions might react with nucleophilic sites of cellular macromolecules and so contribute to both the pharmacology and toxicology of N-heterocyclic compounds. Other pathways for the formation of lactam metabolites involve the internal cyclization of precursor metabolites, e.g. the self-condensation of an aldehyde group (formed during metabolism) with a neighboring amide group. However, spontaneous ring closures of amino acids to form lactams seem unlikely since it would be anticipated that the amino acid residue would exist as a stable zwitterion under physiological conditions. Thus, it is unlikely that lactams will undergo futile metabolism via hydrolytic ring opening followed by ring closure. Under extreme conditions such unanticipated ring closures may occur and the conditions of metabolite isolation may contribute to the occurrence of artifacts.

In vitro and in vivo studies on the metabolism of tirofiban.

Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either (3)H-label incorporated into the phenyl ring of the tyrosinyl residue or (14)C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [(14)C]tirofiban. However, male rat liver microsomes converted a limited amount of the substrate to a more polar metabolite (I) and a relatively less polar metabolite (II). The formation of I was sex dependent and resulted from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was identified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridine-5'-diphospho-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [(14)C]tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 73%, respectively. Metabolite I and unchanged tirofiban represented 70 and 30% of the urinary radioactivity, respectively. Tirofiban represented >90% of the biliary radioactivity. At least three minor biliary metabolites represented the remainder of the radioactivity. One of them was identified as I. Another was identified as II. When dogs received 1 mg/kg i.v. of [(3)H]tirofiban, most of the radioactivity was recovered in the feces as unchanged tirofiban. The plasma half-life of tirofiban was short in both rats and dogs, and tirofiban was not concentrated in tissues other than those of the vasculature and excretory organs.