Rydberg-resolved resonant inelastic soft x-ray scattering: dynamics at core ionization thresholds.

Resonant inelastic x-ray scattering spectra excited in the immediate vicinity of the core-level ionization thresholds of N2 have been recorded. Final states of well-resolved symmetry-selected Rydberg series converging to valence-level ionization thresholds with vibrational excitations are observed. The results are well described by a quasi-two-step model which assumes that the excited electron is unaffected by the radiative decay. This threshold dynamics simplifies the interpretation of resonant inelastic x-ray scattering spectra considerably and facilitates characterization of low-energy excited final states in molecular systems.

Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs.

The aim of this study was to investigate the effect of ionization on drug transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) transported basic model drug across Caco-2 cell monolayers was investigated. Both drugs had pK(a)values in the physiological pH range. The permeability coefficients (P(c)) of the model drugs were obtained at varying apical buffer pHs, thus varying the degree of drug ionization (from 5 to 95%). The relationship between P(c) and the fraction of the drug in un-ionized form (f(u)) was analyzed to delineate the permeability coefficients of the un-ionized (P(c,u)) and ionized (P(c,i)) forms of the drugs. Theoretical estimates of the pK(a) values were also calculated from ionization energies for each model compound. For both drugs, a linear increase in P(c) was observed with increasing f(u). Transport of the un-ionized form was 150- and 30-fold more rapid than transport of the ionized form for alfentanil and cimetidine, respectively. However, when f(u) <0.1, the contribution of the ionized form was significant. Because f(u) is <0.1 over the entire physiological pH range for a large number of drugs, these results will have implications on predictions of in vivo intestinal drug absorption both from in vitro studies in cell cultures and from computed structural properties of drug molecules.

Paracellular drug transport across intestinal epithelia: influence of charge and induced water flux.

The influence of drug charge and transepithelial water flux on passive paracellular drug transport was investigated in Caco-2 cell monolayers and rat ileal mucosa in vitro. Three small hydrophilic compounds with different net charges (creatinine, erythritol and foscarnet) were used as model drugs. A hypotonic glucose-rich solution was applied apically to induce epithelial absorption of water. In the Caco-2 monolayers, permeability to creatinine (positively charged) was 25-fold greater than to foscarnet (negatively charged), indicating a pronounced cation selective paracellular permeability. During apical exposure to the hypotonic glucose-rich solution, transport of all model drugs increased in both the absorptive and secretory directions. This enhanced transport coincided with a decrease in transepithelial resistance. Further, fluorescence and transmission electron microscopy indicated dilatations of the paracellular spaces but no damage to the cell membranes. These findings suggested that the enhancement in drug transport was attributable to increased paracellular tight junction permeability rather than to "solvent drag". In the ileal segments, mucosal exposure to the hypotonic glucose-rich solution had no effect on transepithelial resistance and only a marginal increase in drug transport was observed. Taken together, the modest absorption enhancement demonstrated in the in vitro models agrees with results obtained in vivo, supporting the conclusion that a more pronounced disruption of the tight junction barrier than that obtained through stimulation of epithelial absorption of water is required for efficient enhancement of paracellular intestinal drug absorption.

Diffusion of drugs in native and purified gastrointestinal mucus.

The mucus layer covering the surface of the gastrointestinal tract may act as a barrier to drug absorption. The aim of this investigation was to study the self-diffusion coefficients of model drugs with different physicochemical properties in gastrointestinal mucus. An in vitro method was used to determine the self-diffusion coefficients of radiolabeled model drugs in different diffusion media. Glucosamine, mannitol, glucuronic acid, glucose, metoprotol, antipyrine, propranolol, hydrocortisone, and testosterone, which display large differences in charge and octanol/water distribution ratios (K), were used as model drugs. The diffusion coefficients of model drugs were compared in phosphate buffer (PB), native pig intestinal mucus (PIM), and purified pig gastric much (PPGM). PIM was not purified and therefore contained all the original components of native mucus, whereas PPGM contained only high molecular weight mucin molecules. Charge had only minor effects on the diffusion coefficients of the model drugs. Lipophilicity, however, had a much larger effect, the largest decrease in diffusion coefficient, 58%, was observed for testosterone in PIM. A negative relationship between the diffusion coefficient and log K was observed in PIM, but no relationship was observed in PPGM and PB. In contrast, the diffusion coefficients for two larger molecules of comparable size, the lipophilic peptide cyclosporin and the hydrophilic peptide D-arginine vasopressin, were markedly reduced in PIM. In conclusion, the most important physicochemical characteristic influencing the diffusion coefficient of most drugs in gastrointestinal mucus appears to be lipophilicity, whereas molecular size appears to have more influence for larger peptide drugs.