Metabolism lactones

This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the Af-methylphth-alideisoquinolinium salts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type jft-elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo adds may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type 85,86), which seem to be the final products of the metabolism of phthalideiso-quinoline alkaloids. 

Di Marzo V, Cimino G, Sodano G, Spinella A, Villani G, A novel prostaglandin metabolic pathway from a marine mollusc prostaglandin 1,15-lactones. 7th Internation Conf, on Prostaglandins and related compounds, 28 May-1 June 1990, Florence, Italy, p 13... 

Ascorbic acid, which is closely related to the sugars and is no doubt derived from them in the metabolism of the cells of plants, has been shown to be identical with vitamin- C (Szent-Gyorgyi). It has the constitution of a lactone of a-keto-i-gulonic acid (W. N. Haworth, T. Reichstein) ... 

OH 0, v 0 A r-(3-hydroxybutyryl)-L-homoserine lactone, HBHL or 3-OH, C4-HSL Vibrio harveyi Xenorhabdus nematophilus Bioluminescence, polyhydroxybutyrate metabolism. Virulence, extracellular lipase. 

Scheme 2 shows the biosynthesis ofN-(3-oxooctanoyl)-L-homoserine lactone by Tral protein from Agrobacterium using 3-oxooctanoyl-ACP, derived from fatty acid metabolism, as a substrate [29, 33]. Recently, the first crystal structure of a LuxI protein homologue [34] has provided new insights into the function of AHL synthases which will aid the design of novel inhibitors of AHL biosynthesis. 

Non-redox reactions where water is formed as a product are reactions of dehydration. Such reactions can occur between two substrate molecules, or they can involve two functional groups in a single substrate, either creating a new bond (e.g., lactone formation), or transforming a single into a double bond. In xenobiotic metabolism, dehydration is usually in dynamic equilibrium with hydrolysis or hydration and is of relatively modest significance (Chapt. 11). 

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). 

Lactone ring opening can be both enzymatic and nonenzymatic, but it appears that the two mechanistic routes are seldom distinguished in metabolic studies [2], Thus, a number of the reports published on metabolism of lactones assume enzymatic hydration and do not examine what the relative contribution of nonenzymatic processes may be. Like for lactonization reactions, only very few in vitro biochemical studies address the question of relative enzymatic contribution and mechanism. 

These various examples underline various aspects of the metabolism and disposition of lactones in connection with their pharmacological or toxicological activities. Other cases also exist, namely the lactone prodrugs to be presented in Chapt. 8. 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

Fig. 10.16. Comparison of the metabolism of A4-valproic acid (10.54), a metabolite of valproic acid, with that of ethyl A4-valproate (10.57), a synthetic analogue. Both compounds undergo cytochrome P450 catalyzed oxygenation to form the corresponding epoxides (10.55 and 10.58, respectively). The former reacts intramolecularly to form the lactone 10.56 and is not detectably a substrate for epoxide hydrolase. Epoxide 10.58, in contrast, is a substrate for epoxide hydrolase, forming the diol 10.59, which, in turn, carries out an intramolecular nucleophilic attack to form lactone 10.56 [136],...

Thiol elimination to create a C=C bond is also seen in the metabolism of spironolactone (11.101, Fig. 11.13) [131]. This diuretic drug undergoes a number of metabolic reactions in humans, one of which is ready hydrolysis at the thioester bond to yield deacetyl-spironolactone (see Chapt. 7). This reaction is in competition with other pathways such as lactone hydrolysis, S-oxygenation, and dethioacetylation. The latter reaction is the one of interest here, since the elimination of CH3CO-SH transforms the C(5)-C(6) bond into a C=C bond to produce the active metabolite canrenone (11.102, Fig. 

The most common cyclization reactions in drug metabolism proceed with elimination of a H20 molecule. These reactions produce lactams, lactones, cyclic Schiff bases, and even more-complex metabolites. 

A similar metabolic pathway has been characterized in the rat for phenylbutazone, whose y-hydroxylated metabolite (11.159) slowly attained equilibrium with its tautomeric 6-lactone [168], The two tautomers together represented one-third of the dose in 48 h urine. 

These findings led to the proposition that the veratryl alcohol is degraded via the quinone intermediates (Figure 5) to CO2 through a series of transformations involving lignin peroxidase, perhydroxy radicals and the NADP-dependent aryl alcohol oxidoreductase. Veratraldehyde, the major product of lignin peroxidase catalyzed veratryl alcohol oxidation, is rapidly reduced back to veratryl alcohol it is the further metabolism of the side products of the oxidative process, viz. the quinones and lactones, that drives the overall transformation towards completion (34). 

Metabolism - It is likely that the metabolism of orlistat occurs mainly within the Gl wall. In obese patients, 2 metabolites. Ml (4-member lactone ring hydrolyzed) and M3 (Ml with N-formyl leucine moiety cleaved), accounted for approximately 42% in plasma. 

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