An analysis of the biopharmaceutical behaviour of proton pump inhibitors with different physicochemical properties.

At present, little information on the biopharmaceutical behaviour of proton pump inhibitors (PPIs) describing their absorption and biodistribution in vivo has been reported because the extreme instability of PPIs in the gastrointestinal environment makes it difficult to analyze such behaviour. In this work, a modified rat in situ intestinal perfusion model was employed to investigate absorption in the gastrointestinal tract and subsequent biodistribution of several PPIs (ilaprazole, esomeprazole and rabeprazole), which have different physicochemical properties. Our data indicated that PPIs exhibited significantly enhanced absorption rates in the whole intestine, including the duodenum, jejunum, ileum and colon, corresponding to the increase in the oil-water partition coefficient (LogP). PPIs and corresponding salt types showed no obvious differences in absorption, implying that solubility changes in the PPI have little effect on its absorption in the gastrointestinal tract. Among these PPIs, ilaprazole presented a more stable intestinal absorption behaviour, as well as more distribution and longer residence time in the stomach by HPLC-MS/MS analysis and radioactivity counts after 14C radiolabelling. These results may be useful information for PPI optimization and oral formulation design.

The study of intestinal absorption and biodistribution in vivo of proton pump inhibitors.

The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established: through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

Selective Intratumoral Drug Release and Simultaneous Inhibition of Oxidative Stress by a Highly Reductive Nanosystem and Its Application as an Anti-tumor Agent.

Excessive oxidative stress is always associated with the serious side effects of chemotherapy. In the current study, we developed a vitamin E based strongly reductive nanosystem to increase the loading efficiency of docetaxel (DTX, DTX-VNS), reduce its side toxicity and enhance the antitumor effect. Methods: We used Förster Resonance Energy Transfer (FRET) to reveal the in vivo and in vitro fate of DTX-VNS over time. All FRET images were observed using the Maestro imaging system (CRI, Inc., Woburn, MA) and Fluo-View software (Olympus LX83-FV3000). Results: Through FRET analyzing, we found that our nanosystem showed a selective rapider release of drugs in tumors compared to normal organs due to the higher levels of ROS in tumor cells than normal cells, and the accumulation of DTX at tumor sites in the DTX-VNS group was also notably more than that in the Taxotere group after 24 h injection. Meanwhile, DTX-VNS had a prominently stronger anti-tumor effect in various models than Taxotere, and had a synergistic effect of immunotherapy. Conclusions: Our work presented a useful reference for clinical exploration of the in vivo behavior of nanocarriers (DTX-VNS), inhibition oxidative stress and selective release of drugs at tumor sites, thus reducing the side effects and enhancing the anti-tumor effects.

Quantitative structure-selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists.

Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure-selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of pK(i)(M1), pK(i)(M2) and p[K(i)(M2)/K(i)(M1)] (pK(i)(M2)-pK(i)(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r(2) (r(cv)(2)), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[K(i)(M2)/K(i)(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).

Minimal nuclear pore complexes define FG repeat domains essential for transport.

Translocation through nuclear pore complexes (NPCs) requires interactions between receptor-cargo complexes and phenylalanine-glycine (FG) repeats in multiple FG domain-containing NPC proteins (FG-Nups). We have systematically deleted the FG domains of 11 Saccharomyces cerevisiae FG-Nups in various combinations. All five asymmetrically localized FG domains deleted together were non-essential. However, specific combinations of symmetrically localized FG domains were essential. Over half the total mass of FG domains could be deleted without loss of viability or the NPC's normal permeability barrier. Significantly, symmetric deletions caused mild reductions in Kap95-Kap60-mediated import rates, but virtually abolished Kap104 import. These results suggest the existence of multiple translocation pathways.