Non-Systemic Drugs: A Critical Review

Abstract

Non-systemic drugs act within the intestinal lumen without reaching the systemic circulation. The first generation included polymeric resins that sequester phosphate ions, potassium ions, or bile acids for the treatment of electrolyte imbalances or hypercholesteremia. The field has evolved towards non-absorbable small molecules or peptides targeting luminal enzymes or transporters for the treatment of mineral metabolism disorders, diabetes, gastrointestinal (GI) disorders, and enteric infections. From a drug design and development perspective, non-systemic agents offer novel opportunities to address unmet medical needs while minimizing toxicity risks, but also present new challenges, including developing a better understanding and control of non-transcellular leakage pathways into the systemic circulation. The pharmacokinetic-pharmacodynamic relationship of drugs acting in the GI tract can be complex due to the variability of intestinal transit, interaction with chyme, and the complex environment of the surface epithelia. We review the main classes of non-absorbable agents at various stages of development, and their therapeutic potential and limitations. The rapid progress in the identification of intestinal receptors and transporters, their functional characterization and role in metabolic and inflammatory disorders, will undoubtedly renew interest in the development of novel, safe, non-systemic therapeutics.

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

“…Even at a high dose of 150 mg/kg daily in mice, plasma levels only reached an average of 3.9 ± 1.5 μM (Table 1). This could prove to be a valuable asset for BKI 1369 as a potential therapy, as low systemic exposure will most likely alleviate many of its potential toxicity liabilities (Charmot, 2012). With therapeutic doses only reaching plasma concentrations of 5 μM or less in mice, rats and calves, CNS toxicity is less likely, as brain tissue concentrations of BKI 1369 remain approximately equal to its plasma concentrations and is eliminated from the brain at the same rate as plasma.…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…A solution would be to combine enteric blockade of NHE3 with intake of enough resin to bind the excess water. 49,50 Unfortunately, complete analysis of fecal composition and changes in body weight was not reported in this study.…”

From covalent bonds to eco-physiological pharmacology of secondary plant metabolites

“…It is now evident though, that almost all drugs and other bioactive molecules as well as their physiological or pharmacological targets are potentially polyvalent and promiscuous, and that structurally diverse and multi-targeted secondary plant metabolites could represent potential drug leads [32][33][34]. However, the mainstream of modern drug discoverers still continue to overlook the fact that blood levels of a given drug or bioactive agent and their metabolites are not necessarily very reliable predictors of their therapeutically interesting bioactivity profiles, or that structurally diverse secondary plant metabolites could be considered as drug leads for so called "nonsystemic drugs" [35,36]. Nutritional researchers, ecologists and phytopharmacologists have long recognized that the non-systemic effects of edible and other phytochemicals and other substances could be used for prevention and cure of diseases, and that their bioaccessibility plays a more decisive role in dictating their efficacy than their oral bioavailability (as defined by their observed blood levels after oral dosing) [37][38][39].…”