Comparative study of human intestinal and hepatic esterases as related to enzymatic properties and hydrolizing activity for ester-type drugs.

Inoue, Michiko; Morikawa, Masako; Tsuboi, Masahiro; Ito, Yoshimasa; Sugiura, Masahiro

doi:10.1254/jjp.30.529

Cited by 46 publications

(16 citation statements)

References 15 publications

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“…They found that in the intestine and liver homogenates, the hydrolysis rate constants tended to increase in proportion to increases in acyl chain length (one to three carbons) of the prodrugs. The same tendency was reported for a purified esterase from human intestine and liver using a-naphthyl esters as substrates [46]. In the case of the alkyl group there is a similar increase in affinity and reactivity up to a maximum of four to six carbons; whereas a further increase in the alkyl chain length produced a drop in affinity and reactivity [47].…”

Section: Hepatic Stability Of Fumaratessupporting

confidence: 72%

Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters

Werdenberg¹,

Joshi

Wolffram

et al. 2003

Biopharm & Drug Disp

113

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Psoriasis is a chronic inflammatory skin disease. Its treatment is based on the inhibition of proliferation of epidermal cells and interference in the inflammatory process. A new systemic antipsoriasis drug, which consists of dimethylfumarate and ethylhydrogenfumarate in the form of their calcium, magnesium and zinc salts has been introduced in Europe with successful results. In the present study, a homologous series of mono- and diesters of fumaric acid has been studied with respect to the sites and kinetics of presystemic ester degradation using pancreas extract, intestinal perfusate, intestinal homogenate and liver S9 fraction. In addition, intestinal permeability has been determined using isolated intestinal mucosa as well as Caco-2 cell monolayers, in order to obtain estimates of the fraction of the dose absorbed for these compounds. Relationships between the physicochemical properties of the fumaric acid esters and their biological responses were investigated. The uncharged diester dimethylfumarate displayed a high presystemic metabolic lability in all metabolism models. It also showed the highest permeability in the Caco-2 cell model. However, in permeation experiments with intestinal mucosa in Ussing-type chambers, no undegraded DMF was found on the receiver side, indicating complete metabolism in the intestinal tissue. The intestinal permeability of the monoesters methyl hydrogen fumarate, ethyl hydrogen fumarate, n-propylhydrogen fumarate and n-pentyl hydrogen fumarate increased with an increase in their lipophilicity, however, their presystemic metabolism rates likewise increased with increasing ester chain length. It is concluded that for fumarates, an increase in intestinal permeability of the more lipophilic derivatives is counterbalanced by an increase in first-pass extraction.

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Section: Hepatic Stability Of Fumaratessupporting

confidence: 72%

Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters

Werdenberg¹,

Joshi

Wolffram

et al. 2003

Biopharm & Drug Disp

113

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“…Individual enzymes belonging to this class have been shown to have broad pH-activity profiles with optima between 6.0 and 8.5 (Stoops et al 1975;Hashinotsume et al 1978). The principal carboxylesterase from human liver has been reported to have optimal activity at pH 6.5 (Inoue et al 1980). Therefore, our incubation conditions were appropriate not only as far as substrate stability is concerned, but are likely to be compatible in terms of enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes Differential hydrolysis for the lactone and carboxylate forms

Haaz

Rivory

Riche

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Irinotecan (CPT-11) is a new camptothecine derivative presently in development for the treatment of several advanced malignancies. It is converted in vivo to a highly potent metabolite, SN-38, by carboxylesterases. All camptothecine derivatives undergo lactonolysis in a pH-dependent reversible manner, generating inactive carboxylate forms. We have investigated in vitro the kinetics of transformation of CPT-11 to SN-38 by human liver microsomes originating from several donors. Microsomes from seven livers were studied individually or as a pooled preparation. CPT-11, either in its lactone or its carboxylate form, was added at a range of concentrations. The SN-38 formed was measured by HPLC with fluorometric detection. In the deacylation-limited carboxylesterase reaction, the linear steady-state kinetics between 10 and 60 min were determined. At all concentrations of CPT-11, the steady-state velocity of SN-38 formation as well as the intercept concentrations of SN-38 were about 2-fold higher when the substrate was under the lactone form than under the carboxylate form. We estimated the values (+/-SD) of K'm and Vmax to be 23.3 +/- 5.3 microM and 1.43 +/- 0.15 pmol/min/mg for the lactone and 48.9 +/- 5.5 microM and 1.09 +/- 0.06 pmol/min/mg for the carboxylate form of CPT-11, respectively. We conclude that the greater rate of conversion of CPT-11 lactone may contribute to the plasma predominance of SN-38 lactone observed in vivo. The inter-individual variation of SN-38 formation was relatively high (ratio of 4 between extreme values) but no large age- or gender-related differences were seen. The effect of twelve drugs of different therapeutic classes (antibiotics, antiemetics, antineoplastics, antidiarrhoeics, analgesics), which could be administered in association with irinotecan in the clinical setting, was evaluated in this system (drug concentration: 100 microM; CPT-11 lactone concentration: 10 microM). Loperamide and ciprofloxacine where the only drugs exerting a weak inhibition of CPT-11 conversion to SN-38.

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“…15,16) hCE-1 and hCE-2 share 48z amino acid sequence identity and are predicted to be glycoproteins of 60kDa. 17,18) Some molecular properties of hCE1 and hCE2 are listed in Table 1. A third, brain-speciˆc CES was isolated in 1999 19) a n dt e r m e dh B r 3( h C E 3 ) .H o w e v e r ,r e l a t i v e l y little characterization of this CES has been reported.…”

Section: Tissue Distribution Of Human Carboxylesterasementioning

confidence: 99%

Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design

Imai

2006

Drug Metabolism and Pharmacokinetics

316

246

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Human carboxylesterase 1 (hCE-1, CES1A1, HU1) and carboxylesterase 2 (hCE-2, hiCE, HU3) are a serine esterase involved in both drug metabolism and activation. Although both hCE-1 and hCE-2 are present in several organs, the hydrolase activity of liver and small intestine is predominantly attributed to hCE-1 and hCE-2, respectively. The substrate specificity of hCE-1 and hCE-2 is significantly different. hCE-1 mainly hydrolyzes a substrate with a small alcohol group and large acyl group, but its wide active pocket sometimes allows it to act on structurally distinct compounds of either large or small alcohol moiety. In contrast, hCE-2 recognizes a substrate with a large alcohol group and small acyl group, and its substrate specificity may be restricted by a capability of acyl-hCE-2 conjugate formation due to the presence of conformational interference in the active pocket. Furthermore, hCE-1 shows high transesterification activity, especially with hydrophobic alcohol, but negligible for hCE-2. Transesterification may be a reason for the substrate specificity of hCE-1 that hardly hydrolyzes a substrate with hydrophobic alcohol group, because transesterification can progress at the same time when a compound is hydrolyzed by hCE-1. From the standpoint of drug absorption, the intestinal hydrolysis by CES during drug absorption is evaluated in rat intestine and Caco2-cell line. The rat in situ single-pass perfusion shows markedly extensive hydrolysis in the intestinal mucosa. Since the hydrolyzed products are present at higher concentration in the epithelial cells rather than blood vessels and intestinal lumen, hydrolysates are transported by a specific efflux transporter and passive diffusion according to pH-partition. The expression pattern of CES in Caco-2 cell monolayer, a useful in vitro model for rapid screening of human intestinal drug absorption, is completely different from that in human small intestine but very similar to human liver that expresses a much higher level of hCE-1 and lower level of hCE-2. Therefore, the prediction of human intestinal absorption using Caco-2 cell monolayers should be carefully monitored in the case of ester and amide-containing drugs such as prodrugs. Further experimentation for an understanding of detailed substrate specificity for CES and development of in vitro evaluation systems for absorption of prodrug and its hydrolysates will help us to design the ideal prodrug.

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Comparative study of human intestinal and hepatic esterases as related to enzymatic properties and hydrolizing activity for ester-type drugs.

Cited by 46 publications

References 15 publications

Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters

Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters

The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes Differential hydrolysis for the lactone and carboxylate forms

Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design

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