Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat

doi:10.1016/S0168-8278(05)80520-3

Journal of Hepatology

Volume 17, Issue 1, 1993, Pages 48-55

https://doi.org/10.1016/S0168-8278(05)80520-3 Get rights and content

The biliary clearances of fluid phase markers like erythritol and mannitol have been used to estimate canalicular bile flow. Larger fluid phase marker molecules like polyethylene glycol (PEG) 900 are excreted more extensively into bile, and it has been suggested that the biliary clearance of these give a more accurate measure of canalicular water flux than those of erythritol and mannitol. In this study, the biliary excretion of PEG 900 was compared with that of mannitol during choleresis induced by either sodium taurocholate or secretin. The biliary excretion of PEG 900 exceeded that of mannitol by a factor of 94. The biliary clearance of these markers was not influenced by secretin-induced choleresis. Using ion-exchange chromatography and fast atom bombardment mass spectrometry (FABMS) it was demonstrated that 26% of the PEG molecules are excreted into bile after oxidation to carboxylic acids, whereas sulphate conjugation is negligible. The majority of the PEG molecules (74%) were secreted unchanged, which supports the hypothesis of a mainly passive movement of PEG with the water flux into bile. FABMS showed an enrichment of larger PEG molecules in bile, which supports a previous finding that among differently sized PEGs the 1074-Da molecules have the highest biliary excretion.

References (27)

ShackletonCHL et al.
Use of Sep-pak^g cartridges for urinary steroid extraction: Evaluation of the method for use prior to gas chromatographic analysis
Clin Chim Acta
(1980)
SvanvikJ et al.
An experimental method for studying in vivo gallbladder absorption
Gastroenterology
(1977)
AlméB et al.
Analysis of metabolic profiles of bile acids in urine using a lipophilic anion exchanger and computerized gas-liquid chromatography-mass spectrometry
J Lipid Res
(1977)
ChadwickVS et al.
Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). I. Chemical analyses and biological properties of PEG 400
Gastroenterology
(1977)
ChadwickVS et al.
Measurement of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). II. Application to study of normal and abnormal permeability states in man and animals
Gastroenterology
(1977)
MaTY et al.
PEG 400, a hydrophilic molecular probe for measuring intestinal permeability
Gastroenterology
(1990)
FrimanS et al.
Biliary excretion of different sized polyethylene glycols in the cat
J Hepatol
(1990)
ForkerEL
Two sites of bile formation as determined by mannitol and erythritol clearance in the guinea pig
J Clin Invest
(1967)
WheelerHO et al.
Canalicular bile production in dogs
Am J Physiol
(1968)
ForkerEL
Bile formation in guinea pigs: analysis with inert solutes of graded molecular radius
Am J Physiol
(1968)

BarnhartJL et al.

Erythritol and mannitol clearances with taurocholate and secretin-induced choleresis

Am J Physiol

(1978)

LewisHM et al.

Secretin enhance erythritol clearance in unanesthetized dogs

Dig Dis Sci

(1982)

FrimanS et al.

Hepatic clearance of polyethylene glycol 900 and mannitol in the pig

Digestion

(1988)

Cited by (34)

To PEGylate or not to PEGylate: Immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives
2022, Advanced Drug Delivery Reviews
Citation Excerpt :
PEG was shown to degrade in the presence of hydrogen peroxide, with the degradation depending on the hydrogen peroxide concentration; the lower the concentration, the slower the degradation [93]. PEG may form hydroperoxides in oxygenated environment [99] and other byproducts such as formate esters and formaldehyde, which may be further oxidized to carboxylates following hepatic excretion [100]. Moreover, PEG formulated biomaterial induced exogenous and intracellular ROS production and can trigger apoptotic pathways [97].
Polyethylene glycol or PEG has a long history of use in medicine. Many conventional formulations utilize PEG as either an active ingredient or an excipient. PEG found its use in biotechnology therapeutics as a tool to slow down drug clearance and shield protein therapeutics from undesirable immunogenicity. Nanotechnology field applies PEG to create stealth drug carriers with prolonged circulation time and decreased recognition and clearance by the mononuclear phagocyte system (MPS). Most nanomedicines approved for clinical use and experimental nanotherapeutics contain PEG. Among the most recent successful examples are two mRNA-based COVID-19 vaccines that are delivered by PEGylated lipid nanoparticles. The breadth of PEG use in a wide variety of over the counter (OTC) medications as well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEG’s immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives.
Absorption, distribution, metabolism and excretion of the biomaterials used in Nanocarrier drug delivery systems
2019, Advanced Drug Delivery Reviews
Citation Excerpt :
For non-biodegradable NCs with diameter > 6 nm, excretion is exclusively into bile. Compounds with low MW are handled by active transport [101] whereas those with higher MW undergo paracellular and transcellular transport [102]. For example, 50 nm polystyrene NCs are primarily eliminated in bile as intact particles [103].
Nanocarriers (NCs) are a type of drug delivery system commonly used to regulate the pharmacokinetic and pharmacodynamic properties of drugs. Although a wide variety of NCs has been developed, relatively few have been registered for clinical trials and even fewer are clinically approved. Overt or potential toxicity, indistinct mechanisms of drug release and unsatisfactory pharmacokinetic behavior all contribute to their high failure rate during preclinical and clinical testing. These negative characteristics are not only due to the NCs themselves but also to the materials of the drug nanocarrier system (MDNS) that are released in vivo. In this article, we review the main analytical techniques used for bioassay of NCs and MDNS and their pharmacokinetics after administration by various routes. We anticipate our review will serve to improve the understanding of MDNS pharmacokinetics and facilitate the development of NC drug delivery systems.
Polyethylene glycols in oral and parenteral formulations - A critical review
2015, International Journal of Pharmaceutics
Citation Excerpt :
Prolonged topical application of PEG based creams to open wounds or damaged skin in burn patients or excessive intravenous infusion of PEG based vehicles has been reported to result in increased serum osmolality, profound metabolic acidosis, hypercalcemia, and renal failure (Bruns et al., 1982; Herold et al., 1982; Laine et al., 1995; McCabe et al., 1959; Sturgill et al., 1982; Tayar et al., 2002). PEGs undergo sequential oxidations by alcohol dehydrogenase and aldehyde dehydrogenase to aldehyde, hydroxy acid, and diacid metabolites (Friman et al., 1993; Herold et al., 1989; Hunt et al., 1982). The presence of glycols and their acid metabolites in the serum are attributed to the increased osmolality and metabolic acidosis.
Polyethylene glycols (PEGs) are frequently employed as vehicles in oral and parenteral dosage forms. PEGs have low toxicity, are miscible with aqueous fluids in all proportions, and dissolve many poorly aqueous soluble compounds. Compounds with poor aqueous solubility and resulting poor bioavailability and considerable individual variability in the absorption were shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in PEGs. The advantages offered by PEGs, however, are not without potential challenges that must also be considered and which are the focus of this review. First, PEGs often may have high solubilizing power for some poorly aqueous soluble compounds, the high affinity of these vehicles for water can potentially lead to precipitation of the dissolved compounds when the formulations encounter an aqueous environment in vitro or in vivo, resulting in reduced bioavailability of the compounds. Second, PEGs, due to the presence of hydroxyl groups in their structures, are reactive with compounds dissolved within, resulting in the formation of degradation products. Third, PEGs, due to the presence of recurring ether groups in their polymer chains, are also inherently susceptible to autooxidative reactions, resulting in the formation of highly reactive products, which degrade several compounds formulated with PEGs. The objective is to review the applications and limitations of PEGs in pharmaceutical dosage forms and discuss solutions to mitigate challenges that may potentially arise from their use.
On the biodegradability of polyethylene glycol, polypeptoids and poly(2-oxazoline)s
2014, Biomaterials
Citation Excerpt :
In the case of POx and POI, the location of initial H-abstraction will define whether the polymer backbone will be degraded (Scheme 3) or whether the side chains will be cleaved off (Scheme 4). In the case of PEG, formate esters and formaldehyde are potential products which may be further oxidized to carboxylates, which where identified by Friman and co-workers as metabolites of PEG after hepatic excretion [61]. In the case of polypeptoids, intermediate hydroperoxides may react via different pathways.
Despite being the gold standard of hydrophilic biomaterials and well known sensitivity of polyethylene glycol (PEG) against oxidative degradation, very little information on the decomposition of PEG under biological oxidative stress can be found in the literature. Poly(2-oxazoline)s (POx) and polypeptoids (POI), two pseudo-polypeptides, have attracted some attention for the use as biomaterials and alternative to PEG with an altered stability against oxidative degradation. All three polymer families are supposedly non-biodegradable, which could be seen as one of their main disadvantages. Here, we present evidence that PEG, POx and POI are degradable by oxidative degradation under biologically relevant conditions. Transition metal catalysed generation of reactive oxygen species (ROS) leads to a pronounced time and concentration dependent degradation of all polymers investigated. While we do not envision oxidative degradation to be of relevance in the short-term usage of these polymers, mid- and long-term biodegradability in vivo appears feasible. Moreover, influence in ROS mediated signalling cascades may be one mechanism how synthetic polymers influence complex cellular processes.
Progress in microRNA delivery
2013, Journal of Controlled Release
MicroRNAs (miRNAs) are non-coding endogenous RNAs that direct post-transcriptional regulation of gene expression by several mechanisms. Activity is primarily through binding to the 3′ untranslated regions (UTRs) of messenger RNAs (mRNA) resulting in degradation and translation repression. Unlike other small-RNAs, miRNAs do not require perfect base pairing, and thus, can regulate a network of broad, yet specific, genes. Although we have only just begun to gain insights into the full range of biologic functions of miRNA, their involvement in the onset and progression of disease has generated significant interest for therapeutic development. Mounting evidence suggests that miRNA-based therapies, either restoring or repressing miRNAs expression and activity, hold great promise. However, despite the early promise and exciting potential, critical hurdles often involving delivery of miRNA-targeting agents remain to be overcome before transition to clinical applications. Limitations that may be overcome by delivery include, but are not limited to, poor in vivo stability, inappropriate biodistribution, disruption and saturation of endogenous RNA machinery, and untoward side effects. Both viral vectors and nonviral delivery systems can be developed to circumvent these challenges. Viral vectors are efficient delivery agents but toxicity and immunogenicity limit their clinical usage. Herein, we review the recent advances in the mechanisms and strategies of nonviral miRNA delivery systems and provide a perspective on the future of miRNA-based therapeutics.
The journey of a drug-carrier in the body: An anatomo-physiological perspective
2012, Journal of Controlled Release
Citation Excerpt :
Unless they possess chemical moieties that can be recognized by hepatocytes, soluble CDCs must undergo fluid-phase endocytosis to transit toward the bile canaliculi [164]. Experiments on isolated perfused rat livers have shown that the biliary excretion of macromolecules (PEG, dextran, inulin and proteins) seems to be independent of molecular weight, from 2 to 500 kDa [163,165]. Cationic and anionic charges on the solutes promote and hinder excretion, respectively [165,166].
Recent advances in chemistry and material sciences have witnessed the emergence of an increasing number of novel and complex nanosized carriers for the delivery of drugs and imaging agents. Nevertheless, this raise in complexity does not necessarily offer more efficient systems. The lack of performance experienced by several colloidal drug carriers during the preclinical and clinical development processes can be explained by inadequate pharmacokinetic/biodistribution profiles and/or unacceptable toxicities. A comprehensive understanding of the body characteristics is necessary to predict and prevent these problems from the early stages of nanomaterial conception. In this manuscript, we review and discuss the anatomical and physiological elements which must be taken into account when designing new carriers for delivery or imaging purposes. This article gives a general overview of the main organs involved in the elimination of nanosized materials and briefly summarizes the knowledge acquired over more than 30 years of research and development in the field of drug targeting.

View all citing articles on Scopus

View full text

Regular PaperHepatic excretion and metabolism of polyethylene glycols and mannitol in the cat

Clin Chim Acta

Gastroenterology

J Lipid Res

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Two sites of bile formation as determined by mannitol and erythritol clearance in the guinea pig

J Clin Invest

Canalicular bile production in dogs

Am J Physiol

Bile formation in guinea pigs: analysis with inert solutes of graded molecular radius

Am J Physiol

Erythritol and mannitol clearances with taurocholate and secretin-induced choleresis

Am J Physiol

Secretin enhance erythritol clearance in unanesthetized dogs

Dig Dis Sci

Hepatic clearance of polyethylene glycol 900 and mannitol in the pig

Digestion

Regular Paper
Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat