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Methods for Studying Drug Absorption: In vitro01:16

Methods for Studying Drug Absorption: In vitro

In vitro experiments are crucial for understanding the transport and absorption of drugs through biological materials. These studies employ varied methods such as the diffusion cell method, the everted sac technique, and the everted ring technique.
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Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
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Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs.

Araz A Raoof1, Zeibun Ramtoola, Brain McKenna

  • 1Preclinical Pharmacology, Elan Drug Delivery, Biotechnology Building, Trinity College, Dublin 2, Ireland. araz.raoof@elan.com

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
|October 24, 2002
PubMed
Summary

Sodium caprate enhances oral absorption of antisense oligonucleotides in pigs. This permeation enhancer

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Area of Science:

  • Pharmacology
  • Drug Delivery
  • Biochemistry

Background:

  • Sodium caprate, a medium-chain fatty acid, is a known enhancer of drug transport across intestinal mucosa.
  • Antisense oligonucleotides (ASOs) are a class of drugs with therapeutic potential but limited oral bioavailability.
  • Chemically modified ASOs, such as phosphorothioates and methoxyethyl modified phosphorothioates, are being developed for improved stability and efficacy.

Purpose of the Study:

  • To evaluate the efficacy of sodium caprate as an oral absorption enhancer for two chemically modified antisense oligonucleotides (ISIS 2503 and ISIS 104838) in a pig model.
  • To assess the pharmacokinetic profile and bioavailability of these ASOs when co-administered with sodium caprate.
  • To determine the dose-dependency and duration of action of sodium caprate's enhancing effect.

Main Methods:

  • An intra-intestinal catheterised pig model was utilized to administer sodium caprate at doses of 25, 50, and 100 mg/kg.
  • Two antisense oligonucleotides, ISIS 2503 (phosphorothioate) and ISIS 104838 (methoxyethyl modified phosphorothioate), were administered orally with sodium caprate.
  • Pharmacokinetic parameters including Tmax, Cmax, and AUC were analyzed. Histopathological evaluation of intestinal tissues was performed.

Main Results:

  • Sodium caprate significantly enhanced the systemic delivery of both ISIS 2503 and ISIS 104838.
  • Absorption of both ASOs was rapid (Tmax ~10 min) and short-lived (below detection by 2 hours) across all tested sodium caprate doses.
  • Pharmacokinetic parameters were not significantly altered by increasing sodium caprate doses. ISIS 104838 demonstrated higher oral bioavailability than ISIS 2503.
  • Sodium caprate itself was rapidly absorbed (Tmax ~7 min) with linear pharmacokinetics and was well-tolerated without adverse histopathological findings.

Conclusions:

  • Sodium caprate effectively improves the oral delivery of antisense oligonucleotides in pigs.
  • The membrane-permeation enhancing effect of sodium caprate is rapid, short-lived, and dose-independent within the tested range.
  • The findings support the potential of sodium caprate as a viable excipient for oral oligonucleotide drug formulations.