ArticlePharmaceutical research2001
Transport of peptidomimetic thrombin inhibitors with a 3-amidino-phenylalanine structure: permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2).
Article in Pharmaceutical research, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 14 citations in OpenAlex.
- Biocompatibility Profile and In Vitro Cellular Uptake of Self-assembled Alginate Nanoparticles.Molecules (Basel, Switzerland) · 2019Article
- Modeling kinetics of subcellular disposition of chemicals.Chemical reviews · 2009Review
- pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: implications for drug-drug interactions.Pharmaceutical research · 2003Article
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Authors and funding
9 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
purposePeptidomimetic thrombin inhibitors derived from Nalpha-(2-naphthylsulfonyl)-3-amidino-phenylalanine with different basic and acidic substituents were investigated with respect to their intestinal transport behavior.
methodsIntestinal permeability coefficients were studied using Caco-2 monolayers and a reversed-phase HPLC method for quantitation.
resultsApparent permeability coefficients Papp of compounds with a free amidino group were in general low (<10 x 10(-8) cm/s) and independent of the structure of the amide part (C-terminus). Polarized efflux, however, was strongly affected by substituents in the amide moiety yielding the following efflux ratios (ER): methylpiperidide (1) (ER 45) > piperidine carboxylic acid methylester (ER 6-11) > piperidine carboxylic acids (ER 1.9-2.9) > piperazide (ER -0.17). Efflux of (1) was temperature-dependent, but independent of the enantiomeric configuration, accompanied by an increase in transepithelial electrical resistance (TEER), and could be reduced by P-gp inhibitors (PSC 833, Cremophor EL) but not by indomethacin. Replacement of the amidine group of (1) by aminomethyl-, amino-, and oxamidine- moieties drastically increased absorptive permeability (46-68 fold) with ER < 3.4. In contrast, the oxamidine with a C-terminal nipecotic acid residue (8) displayed also a temperature dependent efflux- without altering TEER (ER 22). This efflux was sensitive to PSC833/Cremophor EL and indomethacin.
conclusionsBasic and acidic residues of amidino-phenylalanine-derived thrombin inhibitors mediate affinity to intestinal efflux pumps. presumably P-gp and MRP. P-gp mediated efflux was related to a net positive charge and accompanied by an increased TEER. Among the methylpiperide (1) promoieties studied the oxamidino group seems to be very promising in overcoming both transport and efflux problems frequently encountered with peptidomimetics containing amidines.
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