Investigating the bioavailabilities of olerciamide A via the rat's hepatic,gastric and intestinal first‐pass effect models

Olerciamide A (OA) is a new alkaloid isolated from Portulaca oleracea L. that has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons for its low bioavailability, hepatic, gastric and intestinal first‐pass effect models were established, and a rapid, sensitive UHPLC method was validated and applied for the determination after dosing via the femoral, portal, gastric and intestinal routes. As inhibitors of CYP3A and P‐gp, verapamil, midazolam and borneol in low and high dose groups were selected to improve the low bioavailability of olerciamide A. Moreover, a rectal administration method was also carried out to improve the bioavailability of olerciamide A. The results showed that the bioavailability of olerciamide A using hepatic, gastric and intestinal routes were 92.16%, 84.88% and 5.76%, respectively. The areas under the plasma concentration–time curve from zero to infinity (AUC_{0 → ∞}) were increased a little after being dosed with 10 and 30 mg/kg verapamil (p > 0.05), but markedly increased after being dosed with 0.4 and 1.2 mg/kg midazolam as well as 8 and 24 mg/kg borneol (p < 0.05). Besides, the AUC_0 → ∞ values after the lower and upper rectal administrations were separately similar to the intravenous and intraportal administrations. Our study showed that the intestinal first‐pass effect mainly contributed to the low bioavailability of olerciamide A in rats due to it being a substrate of CYP3A and P‐gp as well as to its poor intestinal absorption.     

Pharmacokinetics and bioavailability of diclofenac in the rat.

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.     

Metabolism,oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats

The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro‐intestinal first‐pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K_m and V_max), the propensity for UDPGA‐dependent conjugation compared with NADPH‐dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague‐Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro‐intestinal first‐pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non‐compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration–time profiles for 10 and 25 mg/kg were consistent with high clearance (～3 L/hr/kg) and large volumes of distribution (8–12 L/hr/kg). The disposition was characterized by a terminal half‐life value of 3–4 h. After oral administration the plasma concentration–time profiles demonstrated fairly rapid absorption (t_max～1–2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ～2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first‐pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd.     

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

GL‐V9, a derivative of wogonin, has potent anti‐cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL‐V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL‐V9, an in situ single‐pass perfusion model and a Caco‐2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (F_a × F_g) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (F_{gut wall}) was 98.59 ± 9.74%, while the hepatic bioavailability (F_h) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL‐V9. The effective permeability (P_eff) in the duodenum and jejunum was 1.34 ± 0.50 × 10^?4 and 0.90 ± 0.27 × 10^?4 cm/s, respectively. The high permeability of GL‐V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Cl_{int, CYP450s and UGT} of GL‐V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL‐V9 possesses higher permeability than wogonin and the metabolism of GL‐V9 is related to its disposition in rat intestine and liver.     

Bioavailability of caffeic acid in rats and its absorption properties in the Caco-2 cell model

Context: Caffeic acid (CA) is widely distributed in edible plants, and it is beneficial to human health by exerting various biological effects. The potential pharmacological activities of CA are dependent on its absorption in the gastrointestinal tract.

Objective: To investigate the bioavailability of CA in rats and its absorption properties in the Caco-2 cell model.

Materials and methods: A sensitive LC-MS/MS method was successfully applied to determine CA in rat plasma, perfusate, and Hank's balanced salt solution (HBSS). The absolute bioavailability (F_abs) of CA was obtained after i.v. (2?mg/kg) or i.g. administration (10?mg/kg) to rats. Blood samples (approximately 250?µL) were collected from the jugular vein catheter. Pharmacokinetic parameters were calculated using the 3P97 software (version 2.0 PK software; Chinese Society of Mathematical Pharmacology, Anhui, China). The intestinal absorption of CA was explored by the in situ vascularly perfused rat intestinal preparation. CA (5?mg/kg) was administered into the duodenum. Samples (250?µL) were collected from reservoir at specific times, and the same volume fresh perfusate was replaced. The Caco-2 cell model was applied to measure the permeability of CA from the apical to basolateral side (A?→?B) and from the basolateral to apical side (B?→?A).

Results: The absolute bioavailability (F_abs) of CA was 14.7%, and its intestinal absorption was 12.4%. The P_{app A→B} values of CA were ranging from (4.87?±?1.72)?×?10^?7?cm/s to (5.05?±?0.66)?×?10^?7?cm/s as the concentration varied from 5 to 15?µg/mL.

Conclusion: CA was shown to have low oral bioavailability in rats, low intestinal absorption, and poor permeability across Caco-2 cells.     

Positively-charged microemulsion for improving the oral bioavailability of alendronate: in-vitro and in-vivo assessment

Objectives Alendronate is a poorly absorbed bisphosphonate with an oral bioavailability of 0.7%. In this study, a positively‐charged microemulsion was prepared with the aim of improving the bioavailability of alendronate. Methods The positively‐charged microemulsion was evaluated for physical stability, cellular uptake and permeability enhancement on Caco‐2 monolayers. The bioavailability of alendronate from the microemulsion was compared with the commercially available tablet (Fosmax) for beagle dogs. Key findings The 2.0, 0.4 and 0.2% positively‐charged microemulsion, stable for 4 h after preparation, promoted alendronate transport across the Caco‐2 cells by a factor of 194, 146,and 45.1, respectively, compared with the alendronate solution, though no significant cellular uptake enhancement of alendronate was observed. The permeability enhancement was parallel to the reduction in transendothelial electrical resistance, which indicated the microemulsion modulated the tight junctions and widened the paracellular pathway. In‐vivo results showed that the microemulsion gave the highest alendronate plasma concentration at 502 ng/ml (C_max) after 0.563 h (T_max), while tablets gave a C_max of 152 ng/ml after 0.750 h (T_max). Furthermore, the AUC_0‐∞ of alendronate from the microemulsion increased by 2.82‐fold when compared with the tablets. Conclusions Based on the results, the oral bioavailability of alendronate could be significantly improved by the positively‐charged microemulsion, which opened the tight junctions and thus increased absorption through the paracellular route.     

Comparison of the intestinal absorption and bioavailability of γ-tocotrienol and α-tocopherol: in vitro, in situ and in vivo studies

The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of γ-tocotrienol (γ-T3) and α-tocopherol (α-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of γ-T3 or α-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of γ-T3 in the aqueous phase, the oral bioavailability of α-Tph (36%) was significantly higher than γ-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for α-Tph compared with γ-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for α-Tph compared with γ-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of α-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of γ-T3, suggesting that enhancing its permeability would increase its oral bioavailability.     

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Huperzine A (Hup-A) is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01). The absorption rate constant (K_a) and the apparent permeability coefficient (P_app) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_app of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (C_max) of the blocking model were significantly lower than those of the control model (P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.     

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.The present work is part of a research project developed with a grant for the Plan Nacional de I + D (FAR 90-0092) of the Ministry of Industry and Energy of Spain.     

马尼地平磷脂复合物的表征及肠吸收研究

目的：对马尼地平磷脂复合物进行表征,并考察其体外肠吸收特性。方法：采用紫外分光光度法、差示扫描量热分析法、溶解度法和溶出度测定法对马尼地平磷脂复合物性质进行表征;通过离体外翻肠囊模型考察马尼地平在不同肠段的吸收特性。结果：与原药及原药-磷脂物理混合物比较,磷脂复合物的溶解度、溶出度、油/水分配系数、紫外吸收均有不同程度的改变,磷脂复合物在各肠段部位的转运速率V_t和表观渗透系数P_app均大于原药,其中在空肠的吸收均显著强于其他部位（P<0.01）。结论：马尼地平复合磷脂后,其溶解度、溶出度、肠吸收明显改善,马尼地平磷脂复合物将有利于提高药物的生物利用度。     

Effect of Huang‐Lian‐Jie‐Du‐Decoction on pharmacokinetics of verapamil in rats

Objectives The aim was to investigate the effect of Huang‐Lian‐Jie‐Du‐Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Methods Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD‐treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. Key findings HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC_0–480 of verapamil and a 25% reduction in the AUC_0–480 of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. Conclusions HLJDD displayed a route‐dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first‐pass verapamil metabolism in the intestine.     

芍药苷及芍药苷磷脂复合物胶束在体肠吸收对比分析

目的比较芍药苷（PF）和芍药苷磷脂复合物（PF-PLC）胶束的肠吸收特点,探讨磷脂复合物胶束提高PF生物利用度的作用机制。方法采用大鼠在体单向肠灌流模型,以吸收速率常数（Ka）和有效渗透系数（P_eff）为指标,通过超高相液相色谱（UPLC）测定不同浓度PF原料药和PF-PLC胶束在十二指肠中的肠吸收情况。同时,在灌流液中添加维拉帕米,考察P-糖蛋白（P-gp）抑制剂对PF原料药和PF-PLC胶束肠吸收的影响。结果PF-PLC胶束浓度的提高可显著增加PF的肠道吸收（P＜0.001,P＜0.05）。在灌流液中加入维拉帕米后发现,与单纯PF组比较,PF+维拉帕米组的Ka和Peff值虽有增加的趋势,但无明显统计学差异;与PF-PLC胶束组比较,PF-PLC胶束+维拉帕米组差异也无统计学意义。结论大鼠在体单向肠灌流实验结果显示PF-PLC胶束的吸收主要是被动转运途径,且磷脂复合物胶束的形成显著改善了PF在十二指肠的吸收。维拉帕米的加入对PF-PLC胶束的吸收无显著影响,即PF-PLC胶束的吸收不受外排转运体的影响,这可能是生物利用度提高的原因之一。     

In‐situ absorption,protein binding and pharmacokinetic studies of S002‐853, a novel antidiabetic and antidyslipidaemic flavone derivative in rats

Objectives The aim of the study was to investigate the in‐situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002‐853, which shows pronounced antidiabetic and antidyslipidaemic activity. Methods Quantification of S002‐853 in plasma was performed by the LC‐MS/MS method and in‐situ sample analysis was carried out by the HPLC‐UV method. Key findings The absorption rate constant was 0.274/h in a mild alkaline environment, which S002‐853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 ± 2.58% at a concentration of 1 μg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C_max) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration–time profiles with secondary peaks were observed after oral dose administration. The elimination half‐life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002‐853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation. Conclusions In‐situ study of S002‐853 shows slow absorption from the gastrointestinal tract. S002‐853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.     

体外扩散池法评价银杏酮酯磷脂复合物体外透过性能研究

目的 用体外扩散池法评价银杏酮酯制备成磷脂复合物后经大鼠肠透过性能的变化.方法 选取大鼠不同区段肠包括十二指肠、空肠、回肠和结肠,用体外扩散池法选出银杏酮酯透过性能的最佳区段肠后,再对银杏酮酯原料、银杏酮酯磷脂复合物和杏灵颗粒在最佳区段肠中进行透过性能的比较,用高效液相色谱法测定银杏酮酯中的黄酮醇苷在接收池中的累积透过量,表观渗透系数（Papp）作为指标评价银杏酮酯制备成磷脂复合物后的肠透过性能的变化.结果 银杏酮酯在十二指肠中的透过性最好,其次是空肠,由于一般药物在十二指肠停留的时间较短,所以选择空肠作为最佳区段肠,对银杏酮酯原料和银杏酮酯磷脂复合物的透过性能进行比较,结果银杏酮酯磷脂复合物的表观渗透系数高于银杏酮酯原料和杏灵颗粒.结论 用体外扩散池法对其初步评价,银杏酮酯原料制备成磷脂复合物后,体外肠透过性能比银杏酮酯原料和杏灵颗粒有显著提高,为提高体内生物利用度提供了有利依据.     

Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel

The percutaneous absorption of diclofenac was studied in ten healthy volunteers treated with Emulgel containing 1.16% diclofenac diethylammonium for 8 d as follows: a single application of 5 g Emulgel on days 1 and 8, and two applications d^?1 on days 2–7. Plasma concentration profiles of unchanged diclofenac and urinary concentrations of total diclofenac and metabolites (sum of free and conjugated) were determined. High inter-individual variations in plasma and urine data were recorded, due probably to the permeability and the hydration of the skin. Steady state was reached after 2 d of twice-daily administration. Plasma concentrations were low but remained in the range 10–50 nmol L^?1 over the full day for most of the subjects, indicating prolonged absorption from the application site.     

Intestinal permeability of forskolin by in situ single pass perfusion in rats

The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 μg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability.     

Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs

The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by ¹H NMR with a degree of substitution of Cur of 4.52–10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (～200?nm). In situ single-pass perfusion studies in rats showed that both CsA?+?CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher K_a and P_eff than CsA suspension in the duodenum and jejunum segments (p?< 0.01), which was comparable to verapamil coperfusion effect. Similarly, CsA?+?CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.     

Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers

Little is known about the course of the plasma concentration and the bioavailability of non‐steroidal anti‐inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i.m. applications and regarding their plasma concentration–time course. Twenty‐four healthy human volunteers were treated using a parallel group design (n = 12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by eight consecutive dermal patches every 12 hr to reach steady‐state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, C_max was 0.81 ± 0.11 (mean ± S.E.M.) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3 ± 3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72 ± 0.32 ng/mL for diclofenac and 48.7 ± 6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i.m. applications were 0.22 ± 0.04% for diclofenac and 1.15 ± 0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i.m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC₅₀ values for COX‐1 and COX‐2, explaining the absence of dose‐dependent toxicities.     

Nanoemulsion for Improving the Oral Bioavailability of Hesperetin: Formulation Optimization and Absorption Mechanism

This study aimed to prepare a nanoemulsion vehicle to improve the oral bioavailability of hesperetin. The pseudo-ternary phase diagrams and the RSM were used to optimize nanoemulsion parameters. Compared with hesperetin suspension, the AUC_0-t and C_max of nanoemulsion were increased by 5.67-fold and 2.64-fold, respectively. The proportion of lymphatic transport reached 87.72%, the cumulative absorption amount of jejunum, ileum, and duodenum increased by 1.1-fold, 1.92-fold, and 1.5-fold, respectively. The results implied that hesperetin nanoemulsion could effectively improve the bioavailability of hesperetin by increasing lymphatic transport and enhancing intestinal permeability. Therefore, nanoemulsion is a potential method to improve the bioavailability of hesperetin, which has strong practicability.     

Novel Curcumin Diclofenac Conjugate Enhanced Curcumin Bioavailability and Efficacy in Streptococcal Cell Wall-induced Arthritis

Curcumin-diclofenac conjugate as been synthesized by esterification of phenolic group of curcumin with the acid moiety of diclofenac, and characterized by mass spectrometry, NMR, FTIR, DSC, thermogravimetric analysis and X-ray diffraction analysis. The relative solubility of curcumin-diclofenac conjugate, curcumin and diclofenac; stability of curcumin-diclofenac conjugate in intestinal extract; permeability study of curcumin-diclofenac conjugate using the everted rat intestinal sac method; stability of curcumin-diclofenac conjugate in gastrointestinal fluids and in vitro efficacy have been evaluated. In vivo bioavailability of curcumin-diclofenac conjugate and curcumin in Sprague-Dawley rats, and antiarthritic activity of curcumin-diclofenac conjugate, curcumin and diclofenac in modified streptococcal cell wall-induced arthritis model in Balb/c mice to mimic rheumatoid arthritis in humans have also been studied. In all of the above studies, curcumin-diclofenac conjugate exhibited enhanced stability as compared to curcumin; its activity was twice that of diclofenac in inhibiting thermal protein denaturation taken as a measure of in vitro antiinflammatory activity; it enhanced the bioavailability of curcumin by more than five folds, and significantly (P<0.01) alleviated the symptoms of arthritis in streptococcal cell wall-induced arthritis model as compared to both diclofenac and curcumin.