Lactam metabolites, hydrolysis

What about the susceptibility of lactam metabolites to metabolic hydrolysis to yield the corresponding co-amino acid metabolite Little is... 

One may, therefore, assume that the lactam metabolites formed are rather resistant to hydrolytic degradation and do not contribute significantly to the formation of the co-amino acid derivatives. This is in line with the observation that substituted pyrrolidin-2-ones are generally resistant to metabolic hydrolysis (see Sect. 5.3). 

Caprolactam (5.68, Fig. 5.21) has a seven-membered lactam ring and is a major industrial compound in the production of Nylon , its polymer. This compound shows only moderate levels of toxicity in mice and rats when administered orally. The hydrolysis product 6-aminohexanoic acid (5.69) was a minor metabolite in rats [176]. Hydroxylation in the y-position to yield 5.70 without preliminary hydrolysis of the lactam linkage has been shown to be the major metabolic pathway. This metabolite hydrolyzes in urine to produce 6-amino-4-hydroxyhexanoic acid (5.71), which is in equilibrium with the corresponding lactone (5.72). 

We now examine the metabolic fate of lactam bonds located in rings containing an additional heteroatom, designated here as complex lactams. Our first example is DN-9893 (5.73) a platelet-aggregation inhibitor [177]. Its ring-opened metabolite 5.74 was detected in rat urine after intravenous administration of DN-9893. However, insufficient evidence exists to determine whether hydrolysis of the lactam ring was enzymatic or nonenzymatic. 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

In the metabolism of perindopril (11.146, R = Et), in vivo cyclization to the lactam 11.147 (R = Et) was also observed [160], In monkeys, dogs, and rats, hydrolysis of the ethyl ester group predominated, yielding perindopri-late (11.146, R = H). In humans, perindopril lactam (11.147, R = Et) and per-indoprilate lactam (11.147, R = H) were the major metabolites. Such large interspecies differences seem to exclude artifactual formation of the lactams during sample workup. 

It has been recently reported (109) that use of both Penase and lactamase II hydrolysis and screening assays prior to chromatographic analysis can tentatively classify -lactams into three subgroups the first group includes a ceftiofur metabolite represented by desfuroyl-ceftiofur-cysteine the second, cephapirin and the third, penicillin G, ampicillin, amoxicillin, and cloxacillin. In this approach, portions of aqueous extracts of tissues are treated separately with Penase and lactamase II, and results are compared with those of untreated samples and positive controls. Bioactive ceftiofur metabolites are present, provided that the extracts retain inhibitory activity after Penase treatment but lose activity after lactamase II treatment and are positive in response to the immunochemical Lac-Tek-Cef test but negative to the Lac-Tek-Bl test (113). This approach can eliminate a large number of negative samples and, therefore, increases the efficiency of the assay. 

Disposition in the Body. Readily absorbed after oral administration bioavailability almost 100%. Metabolised by demethylation and subsequent deamination to the active metabolites desme-thylchlordiazepoxide and demoxepam. Demoxepam is further metabolised by hydrolysis with cleavage of the lactam ring and by reduction to desmethyldiazepam (nordazepam) followed by hydroxylation to oxazepam (desmethyldiazepam and oxazepam are also pharmacologically active). About 60% of a dose is excreted in the urine and 10 to 20% is eliminated in the faeces less than 1% of a dose is excreted in the urine unchanged, about 6% is excreted as demoxepam, and the remainder as ring-opened derivatives and glucuronide conjugates of oxazepam and other hydroxylated metabolites. 

Chlordiazepoxide (2) is completely absorbed upon oral administration and reaches peak plasma concentrations in 1-2 h (90). As a highly lipophilic molecule it is 94% bound to plasma proteins (91) and readily penetrates the brain, with CSF levels paralleling unbound plasma levels (92). Chlordiazepoxide has a mean half-life of 15 h. It is metabolized first by oxidative removal of the N-2 methyl group (to give N-desmethylchlordiazepoxide), followed by hydrolysis to the lactam (demox-epam), and reduction of the N-5 oxide to give desmethyldiazepam. All of these metabolites are pharmacologicallyactive. 

Baldwin and co-workers have used a nitroso Diels-Alder reaction as a key step in total synthesis of tabtoxin (17), a metabolite causing leafspot disease in tobacco.41 This group has also prepared tabtoxinine /3-lactam (18), the active principle generated by in vivo enzymatic hydrolysis of 17. 

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