Fei-Fei Yang

Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68-N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient.

In vitro uptake and transport studies of PEG-PLGA polymeric micelles in respiratory epithelial cells

&NA; Polymeric micelles are considered promising carriers for pulmonary drug delivery. Their interaction with the respiratory epithelium, however, is mostly unknown. In the present study, methoxypoly (ethylene glycol) (mPEG)‐poly (lactic‐co‐glycolic acid) (PLGA) micelles containing curcumin acetate (CA) or a mixture of CA and Nile Red (NR) were prepared using the solvent evaporation method. Calu‐3 and NCI‐H441 human respiratory epithelial cell monolayers were used as in vitro models of upper and lower respiratory tract epithelium barrier, respectively, to study the cellular uptake and transport of the vesicles. The results show that Calu‐3 and NCI‐H441 cells internalized micellar particles and that micelles were able to translocate across the cell monolayers. Micelles were more readily internalized into and permeated across Calu‐3 cell monolayers when compared to NCI‐H441 cells. Furthermore, the presence of inhibitors of endocytic processes, such as methyl‐&bgr;‐cyclodextrin, NaN3 and hypertonic sucrose attenuated the cellular uptake and trafficking of micelles. In conclusion, this study demonstrated that mPEG‐PLGA micelles translocate human respiratory epithelium in vitro through clathrin‐, energy‐ and cholesterol‐mediated endocytosis. Graphical abstract Figure. No caption available.

Pharmacokinetic Considerations of Inhaled Pharmaceuticals for Systemic Delivery

BACKGROUND Systemic pulmonary delivery is considered to have advantages over oral or intravenous administration for certain drugs. METHODS In this article, we review the effects of intrinsic drug properties and drug loading carriers on the pharmacokinetic parameters of inhaled drugs in the context of use in systemic pulmonary delivery. RESULTS The delivery of drugs via inhalation can be advisable to achieve a fast onset of action; enhance the systemic bioavailability of drugs with poor oral absorption, including peptides and proteins; avoid invasive administration and improve patient compliance. To optimize the functioning of this delivery system, there is high demand for a systematic understanding of the pharmacokinetic characteristics, which are closely related to the pharmacodynamic and toxicological effects. CONCLUSION The pharmacokinetic parameters of inhaled drug products are affected by many factors, including physiological and pathological variables and the intrinsic drug and formulation properties.

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Cholesterol–PEG comodified poly (N-butyl) cyanoacrylate nanoparticles for brain delivery: in vitro and in vivo evaluations

Abstract This study investigated cholesterol–polyethylene glycol (PEG) comodified poly (ethyleneglycol)-poly (lactide) nanoparticles (CLS-PEG NPs) as a novel, biodegradable brain drug delivery system and included an evaluation of its in vitro and in vivo properties. To this end, coumarin-6 (C6), a fluorescent probe, was encapsulated into CLS-PEG NPs by an emulsion polymerization method. We reported that the use of CLS-PEG NPs led to a sustained drug release in vitro. Additionally, cell viability experiments confirmed their safety. The uptake and transport of CLS-PEG NPs, by bEnd.3 cells (an immortalized mouse brain endothelial cell line), was significantly higher than that of a control C6 solution. An investigation of the uptake mechanisms of different NP formulations demonstrated that cholesterol modifications may be the primary way to improve the efficiency of cellular uptake, wherein macropinocytosis may be the most important endocytic pathway in this process. An investigation of the transport mechanisms of CLS-PEG NPs also implicated macropinocytosis, energy and cholesterol in bEnd.3 cells lines. Following an intravenous (IV) administration to rats, pharmacokinetic experiments indicated that C6-loaded CLS-PEG NPs achieved sustained release for up to 12 h. In addition, IV delivery of CLS-PEG NPs appeared to significantly improve the ability of C6 to pass through the blood–brain barrier: the concentration of C6 found in the brain increased nearly 14.2-fold when C6 CLS-PEG NPs were used rather than a C6 solution. These in vitro and in vivo results strongly suggest that CLS-PEG NPs are a promising drug delivery system for targeting the brain, with low toxicity.

Cytochromes P450 Inhibitory Excipient-Based Self-Microemulsions for the Improved Bioavailability of Protopanaxatriol and Protopanaxadiol: Preparation and Evaluation

Protopanaxatriol and protopanaxadiol exhibit limited oral bioavailability due to the poor solubility and intestinal cytochromes P450-mediated metabolism. This study set out to develop a novel cytochromes P450 inhibitory excipient(s)-based self-microemulsion to encapsulate protopanaxatriol and protopanaxadiol so as to enhance the in vivo bioavailability by inhibiting intestinal metabolism. After screening the inhibitory effect of pharmaceutical excipients on the cytochromes P450-mediated metabolism, two self-microemulsions, SME-1 and SME-2, with similar physicochemical properties were prepared by using either active inhibitory excipients or corresponding inactive excipients. The results showed that no significant difference existed in the profiles of in vitro release, cellular uptake, and permeability in Caco-2 cells, and in vivo lymphatic transport between self-microemulsion-1 and self-microemulsion-2. The in vivo pharmacokinetic experiments indicated that self-microemulsion-1 conferred to significantly higher absolute bioavailability of protopanaxatriol (19.55 %) and protopanaxadiol (100.07 %) than those of the free drug (2.21 % and 23.70 %, respectively) or of self-microemulsion-2 (4.95 % and 45.35 %, respectively). The present work demonstrated that the presence of cytochromes P450 inhibitory excipients in self-microemulsion-1 tended to inhibit intestinal cytochromes P450-mediated metabolism and subsequently improved the oral bioavailability of protopanaxatriol and protopanaxadiol.

Ciclesonide and budesonide suspensions for nebulization delivery: An in vivo inhalation biopharmaceutics investigation

Graphical abstract Figure. No Caption available. Abstract The pulmonary fate of inhaled poorly water‐soluble drugs is not entirely clear. In this study, the main objective was to investigate the in vivo inhalation biopharmaceutics in the aspects of dissolution, mucociliary clearance, absorption and tissue binding using intratracheally administered budesonide and ciclesonide suspensions as model drugs. In doing so, this study first developed a method to differentiate between dissolved and undissolved ciclesonide in the lungs for evaluating in vivo dissolution. Following deposited in rat airways, the drug particles underwent rapid dissolution and mucociliary clearance, leading to the complete removal of drugs from the airways within 2 h and a limited absorption time less than 2 h. Upon dissolution, budesonide and ciclesonide were taken up and retained in the lung tissues for up to 12 h and 24 h, respectively. The in vivo dissolution profiles in the airways exhibited the sameness as the in vitro counterparts in a 0.5% sodium dodecyl sulfate solution as indicated by the similarity factor f2. The efficacy results in a lipopolysaccharide induced lung injury model showed that the duration of local anti‐inflammatory was dependent on the drug levels in the lung tissues, but not on the in vitro/in vivo dissolution and plasma pharmacokinetics. The present results demonstrated that ciclesonide suspension has the potential to achieve once‐daily dosing for nebulization therapy and the in vitro dissolution profile has limited usefulness in predicting in vitro–in vivo correlation.

Improving oral bioavailability of resveratrol by a UDP-glucuronosyltransferase inhibitory excipient-based self-microemulsion

Abstract Self‐microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME‐1 with UGT inhibitory excipients (excipients without inhibitory activities named SME‐2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco‐2 cells as well as in vivo lymphatic distribution between inhibitory SME‐1 and non‐inhibitory SME‐2 were observed. In vivo study demonstrated that the molar ratios of RES‐G/RES were 7.25 ± 0.48 and 5.06 ± 2.42 for free drug and SME‐2, respectively, and the molar ratio decreased to 0.36 ± 0.10 in SME‐1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME‐2 to 76.1% in SME‐1 through modulating the glucuronidation by UGT inhibitory excipients. Graphical abstract Figure. No caption available.

Effects of Ganoderma, Rhodiola and grape seed extracts on the glucuronidation and oral bioavailability of resveratrol in rats

Abstract Herb extracts were shown to inhibit the activity of UDP-glucuronosyltransferases (UGTs) in vitro. However, the actual in vivo effect of the inhibitory ability on oral bioavailability is yet verified. In this study, resveratrol (RES) was used as a model drug to study the effect of three Chinese herb extracts, Ganoderma, Rhodiola and grape seed, on the in vitro and in vivo inhibition of glucuronidation and the in vivo bioavailability of RES. Overall, although herb extracts might show inhibition on glucuronidation of RES in vitro and in vivo, the inhibition of glucuronidation did not necessarily mean to improve the in vivo bioavailability of RES.