Hepatic esterases

M., Ito, Y., Sugiura, M., Comparative study of human intestinal and hepatic esterases as related to enzymatic properties and hydrolyzing activity for ester-type drugs, Jpn. J. Pharmacol. 

Metabolism Oxidation Glucuronidation Hydroxylation N-Demethylation Hydroxylation Plasma and hepatic esterases... 

Pharmacology Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of 2 diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. 

Orally administered oseltamivir phosphate is rapidly absorbed and converted by hepatic esterases to oseltamivir carboxylate. Approximately 80% of an oral dose reaches the systemic circulation as oseltamivir carboxylate, with peak plasma concentrations achieved within 2.5 to 5 hours. The plasma elimination half-life of oseltamivir carboxylate is 7 to 9 hours. Elimination of the parent drug and its active metabolite occurs primarily by active tubular secretion and glomerular filtration. 

Valganciclovir is a monovalyl ester prodrug that is rapidly hydrolyzed to the active compound ganciclovir (see Ganciclovir) by intestinal and hepatic esterases when administered orally. 

Ester-containing anesthetics such as cocaine, benzocaine, and tetracaine are extensively hydrolyzed by plasma esterases in addition to a contribution from hepatic esterases. 

Cleavage of the ester moiety by hepatic esterases transforms Quinapril (Accupril), a prodrug, into quinaprilat, an ACE inhibitor that, in vitro, is about as potent as benazep-rilat. Quinapril is absorbed rapidly (peak concentrations are achieved in 1 hour, but the peak may be delayed after food), and the rate but not extent of oral absorption (60%) may be reduced by food. It is metabolized to quinaprilat and to other minor metabolites, and quinaprilat is excreted in the urine (61%) and feces (37%). Peak concentrations of quinaprilat in plasma are achieved in about 2 hours. 

Perindopril (aceon) Perindopril erbumine is a prodrug, and 30-50% of systemically available perindopiil is transformed to perindoprilat by hepatic esterases. The oral bioavailability of perindopril (75%) is not affected by food. Perindopril is metabolized to perindoprilat and to inactive metabolites (glucuronides of perindopril and perindoprilat, dehydrated perindopril, and diastere-omers of dehydrated perindoprilat) that are excreted predominantly by the kidneys. Peak concentrations of perindoprilat in plasma are achieved in 3-7 hours. Perindoprilat displays biphasic... 

Rats fed alfalfa, bentonite and corn oil supplements were killed at the end of the growth trials and livers were removed for measurement of non-specific hepatic esterase activity (EC 3.1.1.1 Dabich et al. (1968)). Specific activity was expressed as ymoles a-napthol produced/minute/mg protein with protein determined according to Lowry et al. (1951). 

The activity of hepatic esterase (EC 3.1.1.1.) was not significantly affected by dietary alfalfa, bentonite or corn oil. Supplementation of the control diet with 3 yg/g of T-2 toxin also failed to induce this enzyme. 

T-2 toxin is believed to undergo selective C-4 deacetylation by hepatic microsomal carboxyesterase to yield HT-2 toxin (Ohta et al., 1977 Otta et al., 1978). Further metabolism by the same enzyme leads to the stepwise conversion of HT-2 toxin to the more polar metabolites 4-deactylneosolaniol and T-2 tetraol (Yoshizawa et al., 1980a). The lack of effect of T-2 toxin on the activity of heaptic esterase may be due to the non-specific nature of this enzyme. The low dose of toxin may not have been enough to cause substrate induction of the enzyme. The lack of effect of additives on the activity of hepatic esterase adds support to the concept that they do not alleviate T-2 toxicosis by promoting catabolism of the toxin. 

The role of dietary fats in alleviation of T-2 toxicosis is not easily explained. No evidence was gathered to show that dietary fats altered T-2 metabolism. Hepatic esterase activities were unchanged and the degree of unsaturation of lipid had no effect on feed refusal. The fatty acid composition of dietary oils has been shown to alter mixed frunction oxidase activity in rats (Gefferth and Blakovits, 1977) and it was thought that this might influence T-2 toxin metabolism. 

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