Imidazole metabolites

We shall adopt this convention and therefore exclude the last-mentioned groups of acids from this review and shall furthermore exclude other nitrogen-containing acids, such as pyrrolidone-carboxylic acid, indoles, and other metabolites of tryptophan (e.g., anthranilic, hydroxyan-thranilic, kynurenic, xanthurenic, and nicotinic acids), imidazolic metabolites or histidine (e.g., fl-imidazolylpyruvic and urocanic acids), acidic guanidine derivatives, and carbamylated acids, as well as acidic com-... 

Restricting dietary histidine will bring the blood histidine level back to normal and eliminates the urinary imidazole metabolites in patients with histidinemia and urocanase deficiency. However, no urgent treatment is required because of the benign nature of this condition. 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

The outstanding inclusion ability and the carboxylic functions of host I raised the idea of co-erystallizing it with imidazole (Im) which, due to its versatile nature 114), is one of the frequently used components in enzyme active sites, generally presented by histidine. Formally, a system made of imidazole and an acid component may mimic two essential components of the so-called catalytic triad of the serine protease family of enzymes the acid function of Aspl02 and the imidazole nucleus of His57 115) (trypsin sequence numbering). The third (albeit essential) component of the triad corresponding to the alcohol function of Seri 95 was not considered in this attempt. This family of enzymes is of prime importance in metabolitic processes. 

Mass spectrometry indicated this metabolite has undergone oxidative cleavage of the imidazole ring. 

In an attempt to understand further the carcinogenicity of azathioprine, recent work in the authors laboratory has concentrated on the photodegradation of two compounds associated with the drug. l-Methyl-4-nitro-5-thioimid-azole is a metabolite and 5-hydroxy- l-methyl-4-nitroimidazole a hydrolysis product. Both gave, on irradiation at wavelengths greater than 300 nm, 1-methylparabanic acid (248) [152], The primary metabolites of azathioprine had previously been shown to be more potent than the parent drug as photosensitizers. Both 6-mercaptopurine and these imidazoles may play roles in its neoplastic action [151]. 

It has been demonstrated that healthy volunteers have significantly higher levels of the histamine metabolite 1-methyl-imidazole-4-acetlc acid (MelAA) in 24 hour urine samples, when challenged with unwashed cotton,thah with washed cotton. There also are reports of histamine metabolites occurring in the blood of exposed workers (100-102). 

Valsartan (2) is a nonheterocyclic antagonist in which the imidazole of losartan has been replaced with an acylated amino acid. It is a very potent ATj antagonist (IC50 =1.6 nM). There is only one metabolite, valeryl 4-hydroxy valsartan, and it is inactive. The enzymes responsible for valsartan metabolism have not been identihed, but do not seem to be P450 CYP isozymes. Food decreases the absorption by 40%. Valsartan (2) is excreted in the bile (70%) and by the kidneys (30%). [See Chiolero and Burnier (1998).]... 

Histamine is rapidly degraded by oxidative de-samination by the diaminooxidase histaminase, acetylation of the NH2-group, methylation of the ring and oxidation of the methylhistamines by the mono-aminoxidase. The main metabolites are the N-methyl-imidazole acetic acid and the imidazole acetic acid. Histamine interacts with at least four different specific receptors Hi to H4 (see Table 1). 

Cimetidine, the first released H2-blocker, like histamine, contains an imidazole ring structure. It is well absorbed following oral administration, with peak blood levels 45 to 90 minutes after drug ingestion. Blood levels remain within therapeutic concentrations for approximately 4 hours after a 300-mg dose. Following oral administration, 50 to 75% of the parent compound is excreted unchanged in the urine the rest appears primarily as the sulfoxide metabolite. 

It is orally effective broad spectrum imidazole antifungal drug. It is useful in both dermatophytosis and deep mycosis. Oral absorption is facilitated by gastric acidity. It is highly protein bound, metabolised in liver and metabolites are excreted in urine and faeces. Its spectrum is similar to that of miconazole and is more active against Coccidioides. 

Mauritamide A (481), a taurine-containing metabolite, was isolated from the sponge Agelas mauritiana [411]. The taurine-containing alkaloids tauroacidins A (482) and B (483) were isolated from a Hymeniacidon sp. from Okinawa and are tyrosine kinase inhibitors [412]. An imidazole alkaloid, (9 )-clathridine 9-A-(2-sulfoethyl)-imine (484), a taurine derivative of clathridine, was isolated from the calcareous sponge... 

Their antibacterial and mutagenic activity is closely related to the reduction of the 5-nitro group, which is common to all nitroimidazole drugs, and the subsequent formation of reactive metabolites that bind to bacterial DNA, inhibiting DNA and protein synthesis in the microorganisms. Metabolism of 5-nitroimidaz-oles in mammals usually leads to covalently bound residues with a persistent imidazole structure. 

Aromatic azapentalenes have not been found naturally, though an imidazo[4,5-d]imidazole derivative has been implicated in the prebiotic synthesis of purines130 74 (see also Section III,A,l,d). Saturated derivatives occur fairly widely the Senecio alkaloids contain the reduced pyrrolol l,2-a]pyrrole (pyrrolizidine) skeleton,487 and the alkaloid withasomnine is a derivative of pyrrolo[ l,2-6]pyrazole.374,488 The mitomycin antibiotics mentioned earlier in this review (Sections III,B,l,f and III,B,5) contain the pyrrolol l,2-a]indole ring,166,331 and the recently reported fungal metabolite sporidesmin is a saturated derivative of pyrrolo[2,3-6]indole.489... 

It was once thought that the rate of equilibrium of the catalytic acid and basic groups on an enzyme with the solvent limited the rates of acid- and base-catalyzed reactions to turnover numbers of 103 s 1 or less. This is because the rate constants for the transfer of a proton from the imidazolium ion to water and from water to imidazole are about 2 X 103 s 1. However, protons are transferred between imidazole or imidazolium ion and buffer species in solution with rate constants that are many times higher than this. For example, the rate constants with ATP, which has a pKa similar to imidazole s, are about I0 J s 1 M-1, and the ATP concentration is about 2 mM in the cell. Similarly, several other metabolites that are present at millimolar concentrations have acidic and basic groups that allow catalytic groups on an enzyme to equilibrate with the solvent at 107 to 108 s-1 or faster. Enzyme turnover numbers are usually considerably lower than this, in the range of 10 to 103 s-1, although carbonic anhydrase and catalase have turnover numbers of 106 and 4 X 107 s 1, respectively. 

One imidazole- and two thiazole-containing metabolites (462-464) were isolated fom the Australian ascidian Aplydium pliciferum (373). The structures of 462 and 463 were confirmed by synthesis. c/s-5-Hydroxy-4-(4 -... 

The separation of cimetidine and its metabolites is usually carried out by extraction of the biological medium with 1-octanol fran an aqueous alkaline pH solution followed by mixing, addition of an internal standard and centrifugation. The extraction with octanol is repeated and the combined extracts are re-extracted with dilute hydrochloric acid. The aqueous acid solution is then separated, ethanol is added and mixed. This is then followed by saturating the mixture with a large amount of potassium or sodium carbonate to "salt out" the ethanol layer which contains the cimetidine and its metabolite, the sulfoxide. Several different internal standards have been used Metiamide, 1-methyl-3-[2-[[(5-methyl-imidazole-4-yl) -methyl] thio]ethyl]-2-thiourea,19 31 39 (N-cyano-N1-methy1-N"-(3-(4-imidazolyl)-propyl)guanidine32, and 13-hydroxy-theophylline. 0 After extraction the samples are either evaporated to dryness and reconstituted with a known amount of ethanol, injected directly or dissolved in the mobile phase for the HPLC analysis. 

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