Enzymes involved in the bioconversion of ester-based prodrugs

Liederer, Bianca M.; Borchardt, Ronald T.

doi:10.1002/jps.20542

Cited by 325 publications

(262 citation statements)

References 142 publications

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“…14 In the cell, MTX-DG should easily be hydrolyzed with the release of MTX owing to the low substrate specificity of esterases distributed in most tissues in abundance. 15 A short hydrophilic spacer (N-methylenecarbonyl-β-alanine) between the bulky MTX moiety and diglyceride membrane anchor minimizes the disruption of the bilayer packing to load as much as 10 mol% prodrug (to total lipids) into 100-nm liposomes ( Figure 1). The liposomes are stable in buffer for at least 3 weeks; even after freezing, thawing, and ultrasonic treatment, they retain the prodrug in the lipid bilayer.…”

mentioning

confidence: 99%

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Алексеева¹,

Моисеева²,

Onishchenko³

et al. 2017

IJN

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In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5–2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX.

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confidence: 99%

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Алексеева¹,

Моисеева²,

Onishchenko³

et al. 2017

IJN

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“…43; 3x enriched). Like paraoxonase, CES3 belongs to a large esterase family heavily involved in drug metabolism, 192,193 but it has also been shown to have cholesteryl ester hydrolase activity. 194 CES3 is, like paraoxonase, primarily localized to liver microsomes, 191 and was specifically shown to be absent from the cisternal space of phagophores and nascent autophagosomes!…”

Section: Autophagosomal Membrane Proteinsmentioning

confidence: 99%

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

Øverbye¹,

Fengsrud²,

Seglen³

2007

Autophagy

140

117

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“…Historically, many ester-based prodrugs have been developed with the aim of overcoming a number of barriers to drug-like properties (Liederer and Borchardt, 2006;Huttunen et al, 2011). Esterases, which are involved in bioactivation of ester-based prodrugs and inactivation of clinical drugs as well, are typically represented by carboxylesterases (CES) (Satoh and Hosokawa, 2006;Hosokawa, 2008), cholinesterases (Taylor, 1991;Taylor and Radic, 1994), and paraoxonases (Draganov and La Du, 2004).…”

Section: Introductionmentioning

confidence: 99%

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

et al. 2013

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Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM-and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM-and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL.

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Enzymes involved in the bioconversion of ester-based prodrugs

Cited by 325 publications

References 142 publications

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

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