Yin Cheong Wong

Development, characterization and application of in situ gel systems for intranasal delivery of tacrine.

The present study aimed to develop an in situ gel formulation for intranasal delivery of tacrine (THA), an anti-Alzheimers drug. Thermosensitive polymer Pluronic F-127 was used to prepare THA in situ gels. Sol-gel transition temperature (Tsol-gel), rheological properties, in vitro release, and in vivo nasal mucociliary transport time were optimized. The pharmacokinetics and brain dispositions of in situ gel were compared with that from THA oral solution in rats. The in situ gel demonstrated a liquid state with Newtonian fluid behavior under 20 °C, while it exhibited as non-flowing gel with pseudoplastic fluid behavior beyond its Tsol-gel of 28.5 °C. Based on nasal mucociliary transport time, the in situ gel significantly prolonged its retention in nasal cavity compared to solution form. Moreover, the in situ gel achieved 2-3 fold higher peak plasma concentration (Cmax) and area under the curve (AUC) of THA in plasma and brain tissue, but lowered Cmax and AUC of the THA metabolites compared to that of oral solution. The enhanced nasal residence time, improved bioavailability, increased brain uptake of parent drug and decreased exposure of metabolites suggested that the in situ gel could be an effective intranasal formulation for THA.

Intranasal Delivery—Modification of Drug Metabolism and Brain Disposition

ABSTRACTIntranasal route continues to be one of the main focuses of drug delivery research. Although it is generally perceived that the nasal route could avoid the first-pass metabolism in liver and gastrointestinal tract, the role of metabolic conversions in systemic and brain-targeted deliveries of the parent compounds and their metabolites should not be underestimated. In this commentary, metabolite formations after intranasal and other routes of administration are compared. Also, the disposition of metabolites in plasma and brain after nasal administrations of parent drugs, prodrugs and preformed metabolites will be discussed. The importance and implications of metabolism for future nasal drug development are highlighted.

Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions

Introduction: Adverse drug reactions (ADRs) continue to be one of the major causes of failure in drug development while limiting the clinical utilities of many drugs. Contribution of the metabolites formed in vivo to ADRs could be more significant than we might have expected. Areas covered: This review focuses on the relationship between regioselectivity in biotransformation and the ADRs of drugs acting on the central nervous system (CNS). “Regioselectivity” is defined as an exclusively or significantly preferential metabolic reaction at one (or several) site(s) on the substrate molecule. Several CNS drugs and toxicants, of which the metabolites play pivotal roles in ADRs, are summarized in details with the highlight on the roles of metabolism in both toxification and detoxification. The article also discusses in silico predictions of regioselectivity and the formation of toxic metabolites which are becoming increasingly important. Expert opinion: Researchers working on CNS drugs face particular challenges in predicting drug metabolism and potential toxicities of their metabolites. A number of factors contribute to the difficulty of accurate prediction of metabolite disposition in the human brain. Better knowledge of regioselectivity in biotransformation and elucidation of the relationships between biotransformations and ADRs would definitely help designing new compounds with lower bioactivation potentials and rejuvenating the older drugs whose clinical applications are restricted by their ADRs. Administrating drugs by alternative routes such as the intranasal, transdermal, sublingual, and buccal routes could also be a strategy to reduce unwanted metabolite formations.

Herb–drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats

ETHNOPHARMACOLOGICAL RELEVANCE Scutellariae Radix (SR), the dried root of Scutellariae baicalensis Georgi, has a lot in common with non-steroidal anti-inflammatory drugs (NSAIDs). Their similarities in therapeutic action (anti-inflammation) and metabolic pathways (phase II metabolisms) may lead to co-administration by patients with the potential of pharmacokinetic and/or pharmacodynamic interactions. The current study aims to investigate the potential interactions between SR and an NSAID, mefenamic acid (MEF), on the overall pharmacokinetic dispositions, anti-inflammatory effects and adverse effects in rats. MATERIALS AND METHODS The current study simultaneously monitored the pharmacokinetic and pharmacodynamic interactions in a single animal. Four groups of Sprague-Dawley rats (n=7 each) received oral doses of a standardized SR extract (300mg/kg, twice daily), MEF (40mg/kg, daily), combination of SR extract and MEF, and vehicle control, respectively, for 5 days. On Day 5, blood samples were collected after first dose over 24h for the determination of (1) plasma concentrations of SR bioactive components, MEF and its metabolites by LC-MS/MS, and (2) prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) gene expression by ex vivo analyses using LPS-stimulated RAW264.7 macrophage cells, ELISA and real time-PCR. After the rats were sacrificed, stomachs were isolated to assess their gross mucosal damage. Statistical comparisons were conducted using ANOVA and t-test. RESULTS Minimal pharmacokinetic interaction between SR extract and MEF was observed. Co-administration of SR extract and MEF did not significantly alter the plasma concentration-time profile or the pharmacokinetic parameters such as Cmax, AUC0→24, Tmax or clearance. Pharmacodynamic interaction via the COX-2 pathway was observed. The PGE2 level in LPS-stimulated RAW264.7 cells treated with plasma collected from control group over the 24h sampling (AUC0→24[PGE2]) was 191981±8789pg/mlhr, which was significantly reduced to 174,780±6531 and 46,225±1915pg/mlhr by plasma collected from rats administered with SR extract and MEF, respectively. Co-administration of SR extract and MEF further potentiated the PGE2 inhibition, with an AUC0→24[PGE2] of 37013±2354pg/mlhr (p<0.05, compared to SR or MEF group). By analyzing the COX-2 gene expression, SR extract significantly prolonged the COX-2 inhibitory effect of MEF over the 24h (p<0.05). Furthermore, the MEF-induced stomach ulcer after the 5-day treatment, as evidenced by the increased gross ulcer index and sum of lesion length (p<0.05, compared to control), could be alleviated by co-administration with SR extract (p<0.05). CONCLUSIONS Co-administration of SR extract and MEF potentiated the anti-inflammatory effects, alleviated the MEF-induced stomach adverse effect while having minimal pharmacokinetic interactions. Our findings provide insight for combination therapy of SR extract and MEF against inflammatory diseases.

Alterations in the CNS effects of anti-epileptic drugs by Chinese herbal medicines

Introduction: Concomitant use of anti-epileptic drugs (AEDs) and Chinese herbal medicines (CHMs) is increasing globally. However, information summarizing how CHMs might alter the CNS effects of AEDs is lacking. Areas covered: A systematic review of the English-language articles in evidence-based databases was performed. It identified CHMs that interact with AEDs and lead to alterations in the CNS effects of AEDs. This review provides a descriptive summary of the existing information on CHM-induced changes of both the therapeutic and adverse CNS effects of AEDs, including i) anti-epileptic effect, ii) sedative effect, iii) anxiolytic effect and iv) memory impairment effect. The proposed mechanisms behind the interactions are also summarized. Expert opinion: Despite the popularity of both AEDs and CHMs, the availability of information on CHM-AED interactions that could result in altered CNS outcomes is considerably limited. Moreover, there are some insufficiencies in the study designs of the identified reports. More research, including both mechanistic and human studies, with improved study design is necessary to ensure the safety and efficacy of combinational use of AEDs with CHMs.

Pharmacokinetic Comparison Between the Long-Term Anesthetized, Short-Term Anesthetized and Conscious Rat Models in Nasal Drug Delivery

PurposeTo investigate the pharmacokinetic differences between the common nasal delivery models.MethodsIn three different rat models [long-term anesthetized (with nasal surgery), short-term anesthetized (without nasal surgery) and conscious models], tacrine and loxapine were administered via nasal, intravenous and oral routes, and the plasma pharmacokinetics were compared among different models.ResultsSystemic exposures of both drugs and their metabolites were consistently higher in long-term anesthetized model after all routes of administration in comparison to that of conscious model. Nasal bioavailabilities in long-term anesthetized model (tacrine 83%, loxapine 97%) were much higher than that in conscious model (tacrine 10%, loxapine 46%). Further studies on tacrine and its metabolites demonstrated no significant difference in t1/2 between short-term anesthetized and conscious models after all routes of administration; however, long-term anesthetized model showed significantly longer t1/2. Regarding the pharmacokinetic parameters (Cmax, Tmax, AUC, bioavailability) of tacrine and its metabolites, short-term anesthetized model resembled closer to conscious model than long-term anesthetized model.ConclusionsPlasma clearances of tacrine, loxapine, and their metabolites were much slower in the long-term anesthetized model of nasal delivery probably due to suppressed hepatic and renal clearances, while the short-term anesthetized model imposed less impact on tacrine pharmacokinetics and metabolism.

Brain uptake of bioactive flavones in Scutellariae Radix and its relationship to anxiolytic effect in mice

Scutellariae Radix (SR) and its bioactive flavones elicit a variety of effects in the brain. However, the brain uptake of individual SR flavones and its relationship to the elicited effects after SR administration remain unknown. Moreover, previous studies seldom measured pharmacokinetic and pharmacodynamic outcomes simultaneously. In the current study, the brain uptake of six major SR flavones and the anxiolytic behavior following oral administration of a SR extract at two clinically relevant doses (600 and 1200 mg/kg twice daily) were simultaneously investigated in mice (n = 18 per group). Brain and plasma concentrations of the flavones were measured by LC-MS/MS, while the anxiolytic effect was evaluated using the elevated plus maze. To further investigate the mechanism behind the differential brain uptake of the six SR flavones, these flavones were separately administered to mice at an equivalent molar oral dose (n = 6). The brain tissue bindings of the SR flavones were also measured with the in vitro brain slice method. Our results indicated that all six SR flavones including three aglycons (baicalein, wogonin, and oroxylin A) and three glucuronides (baicalin, wogonoside, and oroxyloside) could pass through the blood-brain barrier, with brain concentrations ranging from 7.9 to 224.0 pmol/g. It provided novel evidence that oroxylin A had the highest brain uptake among the six SR flavones regardless of its limited content in SR extract, in which 3.6-3.9% of the administered oroxylin A dose was present in the brain 6 h postdosing and with a brain-to-plasma ratio of 0.42-0.46. Although SR extract contains flavones that are positive modulators of the benzodiazepine binding site of GABAA receptors (baicalein, wogonin, and baicalin), our behavioral study for the first time indicated that SR extract (a mixture of six flavones) did not elicit significant anxiolytic effect at the studied doses. Oroxylin A also demonstrated the highest brain uptake when the six flavones were separately administered to mice, and the highest affinity to brain tissues in the in vitro tissue binding assay. The high brain uptake of oroxylin A, a GABAA antagonist which had been reported to antagonize diazepam-induced anxiolytic effect, might have suppressed the anxiolytic effects of the other flavones and account for the lack of overall anxiolytic effect of SR extract. The current study illustrates the importance of monitoring pharmacokinetics in a behavioral study, particularly for herbal medicines which consist of multiple components that might have different or even opposite pharmacological effects on the same target.

Identification and disposition of novel mono-hydroxyl mefenamic acid and their potentially toxic 1-O-acyl-glucuronides in vivo.

Mefenamic acid (MEF) is a widely prescribed non‐steroidal anti‐inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. The formation of protein‐reactive acylating metabolites such as 1‐O‐acyl‐MEF glucuronide (MEFG) and 3′‐hydroxymethyl‐MEF 1‐O‐acyl‐glucuronide is one proposed cause. In addition to the well‐reported 3′‐hydroxymethyl‐MEF, two mono‐hydroxyl‐MEF (OH‐MEFs) were recently identified in vitro. However, in vivo evidence is lacking and whether these OH‐MEFs would be further glucuronidated to the potentially reactive 1‐O‐acyl‐glucuronides (OH‐MEFGs) is unknown. Utilizing UPLC‐Q‐TOF/MS and LC‐MS/MS, the current study identified, for the first time, four OH‐MEFs and their corresponding OH‐MEFGs from plasma after a single oral administration of MEF (40 mg/kg) to rats, including an OH‐MEF that has not been reported previously. The systemic exposure of these identified metabolites was high, with metabolic to parent AUC0→24h ratios reaching 23–52% (OH‐MEFs) and 8–29% (OH‐MEFGs). These metabolites also had a long systemic exposure time in both single and 5 day multiple oral MEF‐treated rats, with elimination half‐lives between 9 h and > 24 h. In addition to these novel metabolites, the previously reported MEFG was also identified and its systemic exposure was found to be doubled after multiple MEF administrations. These pharmacokinetic results suggest that systemic toxicities caused by the potentially reactive MEFG and OH‐MEFGs could be considerable, especially after repeated MEF treatment. Nevertheless, MEFG and OH‐MEFGs had negligible uptake in the brain, indicating a minimal risk of brain toxicities. Furthermore, an in situ intestinal perfusion study revealed that during MEF absorption, it was extensively metabolized to MEFG while < 5% was metabolized to OH‐MEFs and OH‐MEFGs. Copyright