Research progress in mechanisms of idiosyncratic drug-induced liver injury mediated by inflammatory stress / 药学学报

Idiosyncratic drug-induced liver injury (IDILI) is an unpredictable serious adverse drug reaction, which only occurs in a minority of special susceptible individuals. Although the mechanism of IDILI has not been fully understood, several hypotheses have been proposed to explain the action mode and specific mechanism of IDILI. Of these hypotheses, inflammatory stress hypothesis is one of the most important theories. Under the condition of inflammatory stress, drugs interact with inflammation and mediate the occurrence of IDILI through a variety of mechanisms, which can induce the production of inflammatory cytokines, activate coagulation system, affect the activity of metabolites, induce cholestasis, affect mitochondrial damage, and others. This review will summarize the main mechanisms and influencing factors of IDILI mediated by inflammatory stress, in order to provide a reference for preclinical drug development and basic research on drug-induced liver injury.

Quantification of amlodipine in human plasma by LC-MS/MS method: elimination of matrix effects by improving chromatographic conditions / 药学学报

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of amlodipine in human plasma. The influence of alkalizer, extraction solvent and the chromatographic conditions on the matrix effects was investigated. The stable isotope-labeled amlodipine (amlodipine-d4) was used as an internal standard. Sample preparation involved simple liquid-liquid extraction procedure using methyl tertiary butyl ether. Chromatographic separation was achieved on a Welch Ultimate XB-C18(100 mm×2.1 mm, 3 μm) column with acetonitrile/2 mmol·L-1 ammonium formate (pH 3.0) under gradient condition at a flow rate of 0.6 mL·min-1. Detection was performed using electrospray ionization (ESI) in positive ion multiple reaction monitoring (MRM) mode. The linear range of the analyte was 0.1-20.0 μg·L-1, with the lower limit of quantitation (LLOQ) of 0.1 μg·L-1. The matrix factor for low, medium, high concentration quality control samples and internal standard was (93.9±1.8)%, (95.8±4.9)%, (93.9±1.5)% and (97.9±5.3)%, respectively. The method showed excellent specificity, linearity, intra-day and inter-day accuracy and precision, extraction recovery and stability, according to the CFDA guidance for bioanalytical method validation. The matrix effect was significantly improved through optimizing the chromatographic conditions. This economical, simple, robust, sensitive and specific method is entirely able to meet the requirement of the determination of amlodipine in human plasma samples obtained from bioequivalence studies.

Comparison of self-microemulsifying drug delivery system versus solid dispersion technology used in the improvement of dissolution rate and bioavailability of vinpocetine / 药学学报

The objective of this study is to compare the differences between self-microemulsifying drug delivery system (SMEDDS) and solid dispersion (SD) technology used to improve the dissolution rate and bioavailability of vinpocetine (VIP). The formulation of VIP-SMEDDS was composed of Labrafac, oleic acid, Cremophor EL, Transcutol P, and gum acacia which was used as solid absorbent. VIP-SD was prepared using poloxamer F68 as the carrier. In the solubility test, the solubility of VIP in SMEDDS was 17.3 times as much as that in SD. In the dissolution test, SMEDDS had shown better enhancement and stability in dissolving VIP than SD. When compared to VIP crude powder, the bioavailability of VIP in SMEDDS (VIP-SMEDDS) was 1.89-fold higher, and was less affected by food intake. However, the bioavailability of VIP in SD (VIP-SD) was bioequivalent to that of VIP crude powder. The tissue uptake of VIP-SMEDDS in Peyer's patches, intestine and liver after administration for 2 hours was more favorable than that of VIP-SD, which was 3.7 times higher in Peyer's patches, 2.2 times higher in intestine and 1.5 times higher in liver. In Caco-2 tests, the apparent permeability (P(app)) of VIP-SMEDDS was 2.65 times of that of VIP-SD. The width of the cell tight junctions of Caco-2 cell monolayer treated with VIP-SMEDDS were 9.6-fold wider, but there was no significant change after treatment with VIP-SD, when compared to the blank control. In conclusion, SMEDDS was more efficient than the traditional SD technology in increasing solubility, dissolution, intestinal permeability, lymphatic absorption and bioavailability of the insoluble drugs such as VIP, which is less affected by food intake.

Advances in the study of excipient inhibitors of intestinal P-glycoprotein / 药学学报

P-glycoprotein (P-gp) located in the apicalmembranes of intestinal absorptive cells is an energy-dependent efflux pump which can reduce the bioavailability of a wide range of substrate drugs. There is increasingly interest in enhancing the bioavailability of these molecules by inhibiting intestinal P-gp. A classification of excipient inhibitors of intestinal P-gp nonionic surfactants, poly (ethylene glycol), derivates of beta-cyclodextrin and thiolated chitosan will be presented and then the inhibition mechanism will be discussed. Compared with traditional P-gp inhibitor, excipient inhibitors appear to have minimal nonspecific pharmacological activity, thus potential side effects can be mostly avoided. These excipient inhibitors, which hold the promise of replacing the traditional ones, will be extensively employed to significantly improve the intestinal absorption of poorly soluble and absorbed drugs as a result of P-gp inhibition, and thus to enhance the bioavailability of these drugs. However, the further studies of both the mechanism and clinical application are urgently needed.

The inhibitory effect of pluronic on P-glycoprotein drug pump / 药学学报

To investigate the inhibitory effect of Pluronic on P-glycoprotein (P-gp) drug efflux pump, Caco-2 cells and animal models were established to study the influence of Pluronic on celiprolol transport across Caco-2 cell monolayer and intestinal mucous membrane with verapamil set as a positive control. Drug concentration was measured by HPLC and the apparent permeability coefficient (P(app)), absorption rate constant (k(a)) and the effective permeability coefficient (P(eff)) were calculated. P(app) of basolateral to apical side and apical to basolateral side was (2.10 +/- 0.13) x 10(-6) and (0.333 +/- 0.018) x 10(-6) cm x s(-1), respectively. Transports of celiprolol across Caco-2 cell monolayer were influenced by both verapamil and Pluronic. The absorption constants (k(a)) of celiprolol at duodenum, jejunum, ileum, and colon were (0.09 +/- 0.03), (0.14 +/- 0.04), (0.11 +/- 0.03) and (0.05 +/- 0.02) h(-1), k(a) of celiprolol in verapamil group were (0.14 +/- 0.03), (0.24 +/- 0.02), (0.25 +/- 0.03) and (0.23 +/- 0.02) h(-1), and k(a) of celiprolol in Pluronic group were (0.13 +/- 0.02), (0.22 +/- 0.02), (0.22 +/- 0.03) and (0.20 +/- 0.03) h(-1), respectively. Pluronic showed significant effect on inhibiting P-gp of Caco-2 cell and intestinal mucosa in rats.