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Intestinal absorption enhancement of bioactive peptides and proteins in teleost fish : A novel method of oral drug delivery for prophylaxis or to control non vital functions.

Obiettivo

Experimental evidence exists that, after oral uptake in fish, biodegradable compounds can be targeted to the blood circulation system without significant losses of their bioactivity. The combination of absorption enhancers and digestive enzyme inhibitors resulted in an experimental formulation for oral bioactive peptidergic and proteinergic drug delivery in African catfish, Clarias gariepinus, with a high efficiency compared to intraperitoneal injection. The aim of this project is the improvement of oral drug delivery to initiate the development of a new dietary delivery system for bioactive peptides and proteins. It will be tested firstly for its application to regulate, in a non-stressful and practical way, nonvital functions in teleost fish such as reproduction (maturation, spermiation, ovulation) and growth. Secondly for its application as an oral drug delivery of proteins (recombinant bovine growth hormone and recombinant bovine prolactine) and peptides (gonadotropin releasing hormone).

A standardization of the methods for sampling procedures, analysis of materials and data collection will be worked out in the early phase of this project, in order to develop parallel bioavailability studies. A strategy will be set up for exchange of plasma samples for analysis and of experimental preparation for intestinal uptake studies. Analysis of the uptake will be done using the quantitative (radioimmunoassay (RIA) and enzyme linked immunosorbent assay (ELISA)) and qualitative (radioreceptor assay (RRA)) assays already developed for the measurement of the outlined biologically active compounds whose use is planned in the project.
Research is being carried out with respect to the improvement of oral drug delivery to initiate the development of a new dietary delivery system for bioactive peptides and proteins.

The brain decapeptide, gonadotrophin releasing hormone (GnRH) and 2 polypeptides, the ovine prolactine and the bovine growth hormone were tested. Oral, rectal and the intraperitoneal (IP) routes were compared.

In agastric fish the bioavailability of GnRH after oral or rectal administration with no enhanced gut uptake is 4% of the bioavailability after IP treatment. Using the enhancing formulation it reaches 12.5%. The addition of proteolytic enzyme inhibitors preventing gut degradation allowed better availability reaching around 50% of that obtained after IP. Such increased bioavailability of peptide is correlated with better gonadotrophin secretion and ovulation rates.
In the African catfish, a gastric species, the same formulation including enzyme inhibitors administered by the rectal route had similar effects.
In the other gastric species, the rainbow trout it had not been possible to enhance the gut GnRH uptake using any enhancement formulation.

In all species gut uptake of ovine prolactine and bovine growth hormone without enhancement is rather low compared small peptides, but it remains significant compared to the bioavailability after IP. It can also be enhanced in the carp using the previous enhancing formulation, depending upon the polypeptide.

In carp and catfish, enhancement of peptides gut absorption is not modified in the presence of nutriments, allowing may be the development of a spawning induction technic using the oral route after administration together with food.

Microcapsules containing enhancer, proteolytic enzymes inhibitors, buffer and GnRH, have been produced. In catfish they were as active as the same formulation administered by the rectal route. In rainbow trout an increase of GnRH absorption was indicated.
The main research lines will be carried out through the following phases.

Bioavailability: assessment of bioavailability after oral and rectal intubation of peptides and polypeptides. For the peptide study the gonadotropin hormone releasing hormone analogue (Des-Gly10, D-Arg6, Trp7, Leu8, Pro-ethylamide9)-luteinising hormone releasing hormone (LH-RH) or endogenous gonadotropin releasing hormone is used as a model peptide. 2 model polypeptides are chosen: recombinant bovine prolactine (b-Prl) and recombinant bovine growth hormone (b-GH). Quantification of circulating levels to calculate their bioavailability is carried out by ELISA and RIA.

Bioactivity experiments: a study of the biological activity of peptides after oral uptake in order to monitor nonvital functions in fish. This study involves: the measurement of GtH2 release in carp and trout and its repercussion on the ovulation and spermiation in catfish, trout and carp, after oral uptake and parenteral delivery of a particular s-GnRH-a; and radioreceptor assay of b-Prl and b-GH after oral and parenteral administration.

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Coordinatore

Institut National de la Recherche Agronomique (INRA)
Contributo UE
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Indirizzo
Campus de Beaulieu Avenue du Général Leclerc
35042 Rennes
Francia

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