Paracetamol absorption from different sites in the human small intestine.

Site-specificity in the small intestinal absorption of paracetamol was investigated using a segmental intestinal steady state perfusion technique (triple-lumen tubing system) combined with simultaneous measurements of serum drug concentrations. Dissolved paracetamol was perfused over 160 min into different parts of the small intestine (65-210 cm beyond the teeth). Each of the four healthy subjects was studied twice with a proximal and a more distal site of perfusion. Serum drug concentrations were similar after proximal and distal perfusions. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in both parts of the intestine--proximal: 869 micrograms 30 cm-1 min-1 (95% CI: 659-1079) vs distal: 941 micrograms 30 cm-1 min-1 (794-1088). The absorption rate was related directly to the amount of paracetamol perfused per unit time as well as to the rate of transmucosal water fluxes.     

Profile of P-glycoprotein distribution in the rat and its possible influence on the salbutamol intestinal absorption process

The intrinsic absorption of salbutamol in different intestinal segments of the rat was measured and related with the corresponding intestinal P-glycoprotein (P-gp) expression levels. The apparent absorption rate constants (k(a), h(-1)) observed in each fraction by means of the "in situ" rat gut absorption method after perfusion of a 0.29-mM isotonic solution of salbutamol were used as absorption indexes. In a separate series of studies, a semiquantitative analysis of the mRNA expression of P-gp by means of polymerase chain reaction and Western blot with an antibody raised against the P-gp were also performed. The "in situ" k(a) values determined in the different segments (h(-1)) showed that the absorption is not homogeneous along the intestinal tract, that is, 0.499 +/- 0.054 for colon, 0.474 +/- 0.052 for the proximal segment, 0.345 +/- 0.014 for the mean, and 0.330 +/- 0.023 for the distal fraction. Addition of verapamil to the perfusion fluid did provide a better absorption of salbutamol in the distal segment. The analysis of the mRNA expression and levels of P-gp showed that the enzyme content in each section of the intestine was inversely related to salbutamol absorption.     

Preparation of tripterine nanostructured lipid carriers and their absorption in rat intestine

The purpose of this study was to develop an optimized nanostructured lipid carrier formulation (NLC) for tripterine, and to estimate the potential of NLCs as oral delivery system. Tripterine-loaded NLCs were prepared by the solvent evaporation method. The average drug entrapment efficiency, particle size and zeta potential of the optimized tripterine-loaded NLCs were 78.64 +/- 0.37%, 109.6 +/- 5.8 nm and -29.8 +/- 1.3 mV, respectively. The tripterine-loaded NLCs showed spherical morphology with smooth surface under the transmission electron microscope (TEM). The crystallization of drug in NLC was investigated by differential scanning calorimetry (DSC). The drug was in an amorphous state in the NLC matrix. According to the in vitro release study, the tripterine-loaded NLCs showed a delayed release profile of tripterine. The rat intestinal perfusion model was used to study the absorption of tripterine solution and tripterine-loaded NLCs. The Peff* (effective permeability) of tripterine-loaded NLCs in the duodenum, jejunum, ileum and colon was approximately 2.1, 2.7, 1.1, 1.2-fold higher than that of tripterine solution, respectively. The 10% ABS (percent absorption of 10 cm of intestine) of tripterine-loaded NLCs in the duodenum, jejunum, ileum and colon was approximately 2.2, 2.3, 1.2, 1.3-fold higher than that of tripterine solution, respectively. The intestinal toxicity of tripterine formulated in the NLCs was investigated and compared with the tripterine solution by the MTT assay with Caco-2 cell models. According to the result, the tripterine-loaded NLCs could greatly decrease the cytotoxicity of the drug. In conclusion, the NLC formulation remarkably improved the absorption of tripterine and showed a better biocompatibility.     

The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man.

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L-leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L-leucine decreased the intestinal absorption of levodopa from 40 +/- 19 to 21 +/- 15% but was without effect on the absorption of antipyrine, benserazide and D-glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.     

Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase.

AIM: The aim of this study was to investigate the biliary secretion of rosuvastatin in healthy volunteers using an intestinal perfusion method after administration of 10mg rosuvastatin dispersion in the intestine. METHODS: The Loc-I-Gut tube was positioned in the distal duodenum/proximal jejunum and a semi-open segment was created by inflating the proximal balloon in ten volunteers. A dispersion of 10mg rosuvastatin was administered below the inflated balloon and bile was collected proximally of the inflated balloon. Bile and plasma samples were withdrawn every 20 min during a 4h period (absorption phase) and additional plasma samples were collected 24 and 48 h post-dose. RESULTS: The study showed that there is a substantial and immediate transport of rosuvastatin into the human bile, with the maximum concentration appearing 42 min after dosing, 39,000+/-31,000 ng/ml. Approximately 11% of the administered intestinal dose was recovered in the bile after 240 min. At all time points the biliary concentration exceeded the plasma concentration, and the average bile to plasma ratio was 5200+/-9200 (range 89-33,900, median 2000). We were unable to identify any bile-specific metabolites of rosuvastatin in the present study. CONCLUSION: Rosuvastatin is excreted via the biliary route in humans, and the transport and accumulation of rosuvastatin in bile compared to that in plasma is rapid and extensive. This intestinal perfusion technique offers a successful way to estimate the biliary secretion for drugs, metabolites and endogenous substances during the absorption phase in healthy volunteers.     

Bioavailability of diazepam from aqueous-organic solution, submicron emulsion and solid lipid nanoparticles after rectal administration in rabbits.

The bioavailability of diazepam in rabbits after rectal administration of three formulations: organic-aqueous Relsed rectal solution (containing ethanol, benzyl alcohol and propylene glycol), submicron emulsion and solid lipid nanoparticles (SLN), was studied. Submicron emulsion contained MCT oil (20% w/w), egg lecithin and poloxamer; SLN were prepared with cetyl palmitate 10% w/v and non-ionic emulsifying agent, Plantacare. All formulations contained 4 mg/ml of diazepam and the dose administrated to rabbits was 2 mg/kg. In both submicron preparations nearly the same mean size of the dispersed particles (201-206 nm) and the fraction of the free drug in aqueous phase (0.9-1.5%) was determined. Besides very moderate prolongation of drug release, the submicron emulsion as a vehicle did not alter pharmacokinetics of diazepam when compared with the solution: the mean C(max) was 48.9+/-24.0 and 49.5+/-17.0 ng/ml, and area under the curve was 134.0+/-42.3 and 186.8+/-59.8 ng h/ml, for solution and emulsion, respectively. The low relative bioavailability, 47% compared to the solution, was observed after administration of SLN. Transmission electron microscopy pictures revealed that some of diazepam is present on the surface of the SLN and this fraction was immediately absorbed, while the diffusion of the drug in the solid core was not efficient enough to allow a complete release. It may be concluded that submicron emulsion may be a good choice of an ethanol-free drug formulation, but lipid matrix, which is solid at body temperature, is not advantageous system for diazepam rectal delivery, even if delivered as a submicron dispersion.     

Improvement of cefpodoxime proxetil oral absorption in rats by an oil-in-water submicron emulsion

Absolute bioavailability of cefpodoxime proxetil is both limited by its low solubility in aqueous solution and its intraluminal hydrolysis. The oil-in-water submicron emulsion was proven to be effective in protecting the prodrug from the enzymatic attack in rabbit intestinal washings. The aim of the study was to perform a pharmacokinetic study in conscious rats to confirm o/w submicron superiority in comparison to other oral formulations (hydro-alcoholic solution, suspension and coarse emulsion). The pharmacokinetic study was performed in conscious rats implanted with permanent aortic catheters. A parenteral solution of cefpodoxime was injected via this catheter, and oral formulations were administered orally. The cefpodoxime plasma level was performed by a HPLC validated method. The pharmacokinetic parameters, t1/2, Cmax, tmax, AUC and absolute bioavailability (F) were determined with a non-compartmental analysis. The results show a significant increase of F for submicron emulsion (97.4%) between the other oral formulations. No significant difference of F was found between the other oral formulations, even with the coarse o/w emulsion. The o/w submicron emulsion made the enhancement of the absolute bioavailability of cefpodoxime proxetil possible. This benefit could be explained by the low droplet size of the submicron emulsion which improve the absorption process of the prodrug.     

Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat.

1. The effect of induced water absorption on the intestinal permeability of antipyrine, atenolol and enalaprilat in the proximal jejunum was studied in eight healthy subjects with a regional intestinal perfusion technique. 2. The mean (+/- s.d.) net water flux changed from a secretory status of 1.2 +/- 1.2 ml h-1 cm-1 to an absorptive status of -3.7 +/- 3.5 ml h-1 cm-1 (P < 0.0025) on the introduction of a hypo-osmolar glucose-containing electrolyte solution. 3. The mean permeability values for the three drugs in the eight subjects were unchanged despite the increase in net water absorption (5.7 +/- 3.0 to 7.0 +/- 3.6 x 10(-4) cm s-1 for antipyrine, 0.1 +/- 0.2 to 0.2 +/- 0.2 x 10(-4) cm s-1 for atenolol and 0.3 +/- 0.3 to 0.1 +/- 0.2 x 10(-4) cm s-1 for enalaprilat). One subject showed a large change in the permeability for antipyrine and atenolol in parallel with a large increase in water absorption, but enalaprilat was unaffected. 4. The luminal recovery of PEG 4000 was similar before (100 +/- 4%) and during (101 +/- 7%) induction of water absorption, which indicates that the barrier function of the intestine appears to be maintained during glucose-stimulated fluid absorption in man. 5. We conclude that induced net water absorption in man does not influence the paracellular permeability of hydrophilic drugs or drugs with high molecular weight to any significant extent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uptake of the colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by different segments of the rat gastrointestinal tract: Its implication in colorectal carcinogenesis

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a colon carcinogen in rats. In the present study the absorption of PhIP in the small and large intestine of Fischer 344 rats was determined, and the relevance of the differences in the degree of absorption of PhIP along the gastrointestinal axis for the PhIP-mediated colon carcinogenesis process is discussed. PhIP uptake was low in the different gut sections of Fischer 344 rats, the PhIP tissue levels varying in the following order: proximal jejunum > distal jejunum > proximal colon > distal colon = rectum. Furthermore, abcc2 was mainly expressed in the proximal parts of the small intestine, in particular in the proximal jejunum. Extremely low expression levels were observed in distal jejunum, ileum, caecum and proximal colon, whereas abcc2 was almost not detected in distal colon and rectum. These data, together with previously published results, lend support to the hypothesis that PhIP is taken up in the proximal segments of the small intestine and after being metabolically activated in the liver reaches the stem cell compartment of the colonic crypts via the blood circulation, the crypt cells in the distal colon and rectum being particularly at risk, since these almost do not express abcc2.     

Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2

The first purpose of this study was to investigate the in vivo absorption, biliary secretion, and first-pass effect of fluvastatin following regional intestinal dosing in the rat. We also examined the membrane transport mechanisms and made in silico predictions of the relative importance of various intestinal regions to the human absorption of fluvastatin. Fluvastatin was administered intravenously (2, 10, and 20 micromol/kg) and into the duodenum (1.46, 2.92, 7.32, and 14.6 micromol/kg), jejunum (14.6 micromol/kg), ileum (1.46 and 14.6 mciromol/kg), and colon (1.46 and 14.6 micromol/kg) as a solution to conscious rats. In a separate group of rats, bile was collected after an i.v. dose of fluvastatin (2 micromol/kg). In the Caco-2 model the bidirectional transport of fluvastatin (16 microM) was investigated with and without various efflux inhibitors (verapamil, vinblastine, probenecid, and indomethacin, 160 microM). The human in vivo absorption of fluvastatin from an oral immediate release tablet and that from an oral extended release tablet (both 40 mg) were simulated in GastroPlus. Neither the dose nor the intestinal region influenced the bioavailability of fluvastatin significantly. The rate of absorption was, however, affected by both the dose and the site of administration; duodenum = jejunum > colon > ileum, and higher following the high dose. Increasing the i.v. dose from 2 to 20 micromol/kg decreased the clearance (26 +/- 3 to 12 +/- 1 mL/min/kg), the hepatic extraction (66 +/- 8 to 30 +/- 2%), and the volume of distribution (7.3 +/- 0.3 to 2.1 +/- 0.7 L/kg) for fluvastatin (p < 0.05). Neither bile cannulation nor bile sampling affected the pharmacokinetics. Fluvastatin was secreted into the bile, probably by active transport. The in vitro permeability for fluvastatin was high (>10 x 10(-6) cm/s). Indomethacin, but not the other inhibitors, affected the transport in both directions suggesting mrp2 to be involved. In silico, 93% of the dose was absorbed from the small intestine and 6% from the colon when given as an immediate release formulation. The corresponding values for an extended release formulation were 21% and 74%, respectively. In conclusion, fluvastatin exhibits dose-dependent pharmacokinetics in the rat. The rate of absorption (Cmax, Tmax, and Cmax/AUC(lqc)) from the intestinal tract is both region and dose-dependent in the rat. This may be due to the involvement of mrp2 in the intestine and/or in the liver. These absorption properties have to be considered in the development of an extended release formulation of fluvastatin.     

Regional Intestinal Permeability in Rats of Compounds with Different Physicochemical Properties and Transport Mechanisms

Because the absorption of orally administered drugs depends on intestinal permeability, we have investigated how absorptive capacity varies from the proximal to distal intestine in rats. The effective permeabilities of compounds with a range of physicochemical properties and different absorption mechanisms were estimated by use of a previously validated in-situ, single-pass perfusion model. The low colonic permeabilities of d -glucose and l -dopa indicate the absence or low capacity of the glucose-and amino-acid-transporters in this region. With the exception of the small and moderately lipophilic nonsteroidal anti-inflammatory drug, naproxen, for which permeability was maintained throughout the intestine, the passive intestinal permeabilities for hydrophilic and lipophilic drugs were approximately twice as high in the jejunum and ileum as in the colon. These observations are in accord with those made in recent studies. However, the reasons for the high colonic permeability of non-steroidal anti-inflammatory drugs, and results obtained in previous animal experiments demonstrating that the colon is the region of the intestine with the highest absorptive capacity were not fully clarified. These data show that the permeability to hydrophilic and lipophilic drugs decreases along the intestine, whereas it is maintained throughout the intestine for the small and moderately lipophilic naproxen. Further investigations are required to clarify the interplay between membrane composition, fluidity and permeability under various conditions in different absorption models.     

Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time

Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0–120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.     

Segmental difference and effect of glucose on drug exsorption across the small intestine of rats

An exsorption technique which can assess the transport of a drug from blood to the intestinal lumen was used to study the effects of glucose and to determine the presence of segmental differences in drug transport across the rat small intestinal membrane following intravenous drug administration. The drugs used in the study were un-ionized (sulfanilamide) or ionized (metoclopramide and sulfisoxazole) at the physiological pH (6.5) of rat small intestine. An intestinal segment of 20 cm from the ligament of Treitz to the distal part was used as the jejunum and the same length from the ileocecal junction to the proximal part was regarded as the ileal segment. Isotonic NaCl or glucose was used as the intraluminal perfusate. In the case of sulfanilamide, the exsorption rate remained almost constant during the perfusion of NaCl or glucose and no segmental differences in the exsorption rates were observed. For the weakly basic drug (metoclopramide) the exsorption rate in the jejunum was significantly decreased by glucose. Conversely, for the weakly acidic drug (sulfisoxazole), the exsorption rate in the jejunum was increased during glucose perfusion. In contrast to the effects observed in the jejunum, glucose did not have any significant effect on the exsorption rate of drugs studied in the ileum. These observations might be explained by the intraluminal pH in the respective segments and changes in the pH mediated by glucose perfusion.     

Bisphenol A glucuronidation and absorption in rat intestine.

Bisphenol A, an environmental estrogen, can be leached from plastic tableware and from the coating of food and drink cans, orally exposing human beings to the compound. The present study focuses on the absorption and metabolism of bisphenol A in the rat intestine, as elucidated experimentally by segmented everted intestine. One hour after the application of 2 micromol of bisphenol A to the mucosal fluid, the absorption of bisphenol A was slightly greater in the colon (48.6%) than in the proximal jejunum (37.5%). In the serosal side, unconjugated bisphenol A appeared in small amounts, increasing distally (maximal 1.6 nmol, colon). Large amounts of the bisphenol A glucuronide were then transported into the serosal side, also increasing distally (proximal, 80.4 nmol; distal, 478.4 nmol). The greatest amount of the glucuronide (approximately 573 nmol) was excreted into the mucosal side of the small intestine, whereas in the colon, mucosal excretion was minimal (67.2 nmol). On high-dose application of bisphenol A to the mucosal fluid, the transported unconjugated bisphenol A increased markedly throughout the intestine and colon. These results suggest that bisphenol A in the intestinal lumen is glucuronidated almost exclusively during its passage through the intestinal wall.     

Pharmacodynamics of Insulin Following Intravenous and Enteral Administrations of Porcine-Zinc Insulin to Rats

Previous work from this laboratory showed site-dependent variations in the apparent permeability of insulin as measured using the everted rat gut sac technique, with the greatest permeability in the distal jejunum and the lowest in the duodenum (5). To quantify better the rate and extent of insulin absorption from the small intestine, closed-loop in situ experiments were performed in nondiabetic rats. Results correlated with the everted gut sac technique in that the absolute bioavailability determined in situ was higher for insulin solution administered to the more distal region of the intestine (0.133%) than that absorbed from an earlier portion of the intestine (0.059%). While the difference in regional bioavailabilities was not significant (P = 0.08), the blood glucose response showed highly significant differences (P = 0.0015), with severe and prolonged hy-poglycemia resulting from insulin delivered to the distal jejunum/ proximal ileum. Insulin administered iv followed a two-compartment pharmacokinetic model. Whole-body elimination rate constants were similar for both iv and enteral insulin. Although therapeutic quantities of insulin were absorbed from the distal small intestine, absorption enhancers would be necessary to decrease the dose of insulin required.     

Site‐specific contribution of proton‐coupled folate transporter/haem carrier protein 1 in the intestinal absorption of methotrexate in rats

Objectives Methotrexate is reportedly a substrate for proton‐coupled folate transporter/haem carrier protein 1 (PCFT/HCP1) and reduced folate carrier 1 (RFC1). In this study, we examined the contribution of PCFT/HCP1 and RFC1 in the intestinal absorption of methotrexate in rats. Methods Western blot analysis was carried out to evaluate the protein levels of PCFT/HCP1 and multidrug resistance‐associated protein 2 in brush‐border membrane of rat small intestine. Mucosal uptake of methotrexate was studied in the rat everted small intestine and an in‐situ intestinal perfusion study of methotrexate was also carried out in rats. Key findings In transport studies using everted intestine, the mucosal methotrexate influx rate in proximal intestine at pH 5.5 was significantly greater than that at pH 7.4. Coadministration of folate or its analogues, such as folinate and 5‐methyltetrahydrofolate, substrates for both PCFT/HCP1 and RFC1, significantly suppressed the methotrexate influx at pH 5.5, whereas thiamine pyrophosphate, an inhibitor for RFC1 alone, exerted no significant effect. Western blot analysis showed higher PCFT/HCP1 expression in proximal than distal small intestine. In distal small intestine, methotrexate influx rate was low and was not pH dependent. Also, folate and its analogues exerted no significant effect on methotrexate absorption. Conclusions Based on the present and our previous results, the site‐specific contributions of various transporters including PCFT/HCP1 in methotrexate intestinal absorption were discussed. The variation in luminal pH and the involvement of multiple transporters in methotrexate absorption may cause variation in oral bioavailability among patients.     

Mucoadhesive Microspheres for Gastroretentive Delivery of Acyclovir: In Vitro and In Vivo Evaluation

The aim of the present investigation was to evaluate the potential use of mucoadhesive microspheres for gastroretentive delivery of acyclovir. Chitosan, thiolated chitosan, Carbopol 71G and Methocel K15M were used as mucoadhesive polymers. Microsphere formulations were prepared using emulsion-chemical crosslinking technique and evaluated in vitro, ex-vivo and in-vivo. Gelatin capsules containing drug powder showed complete dissolution (90.5 +/- 3.6%) in 1 h. The release of drug was prolonged to 12 h (78.8 +/- 3.9) when incorporated into mucoadhesive microspheres. The poor bioavailability of acyclovir is attributed to short retention of its dosage form at the absorption sites (in upper gastrointestinal tract to duodenum and jejunum). The results of mucoadhesion study showed better retention of thiolated chitosan microspheres (8.0 +/- 0.8 h) in duodenal and jejunum regions of intestine. The results of qualitative and quantitative GI distribution study also showed significant higher retention of mucoadhesive microspheres in upper GI tract. Pharmacokinetic study revealed that administration of mucoadhesive microspheres could maintain measurable plasma concentration of acyclovir through 24 h, as compared to 5 h after its administration in solution form. Thiolated chitosan microsphere showed superiority over the other formulations as observed with nearly 4.0-fold higher AUC(0-24) value (1,090 +/- 51 ng h/ml) in comparison to drug solution (281 +/- 28 ng h/ml). Overall, the result indicated prolonged delivery with significant improvement in oral bioavailability of acyclovir from mucoadhesive microspheres due to enhanced retention in the upper GI tract.     

环糊精包合作用对在体大鼠肠道P-糖蛋白药泵的影响

目的研究环糊精包合作用对P-糖蛋白底物药物体内吸收的影响。方法以P-糖蛋白底物盐酸小檗碱为模型药物,使用大鼠在体单向肠灌流装置,采用高效液相色谱法分别测定灌流液中盐酸小檗碱和酚红的浓度变化;研究2-羟丙基-β-环糊精(HP-β-CyD)对盐酸小檗碱肠道吸收的影响,以此评价环糊精包合作用对P-糖蛋白药泵的影响。结果盐酸小檗碱、盐酸小檗碱/HP-β-CyD物理混合物及盐酸小檗碱/HP-β-CyD包合物在大鼠空肠的吸收速率常数(Ka)分别为(0.45±0.029)、(0.70±0.087)、(2.39±0.119)×10-2·min-1,有效渗透系数(Peff)分别为(0.43±0.028)、(0.63±0.098)、(2.17±0.145)×10-3min·cm-1。HP-β-CyD对盐酸小檗碱的包合作用促进了大鼠肠道对盐酸小檗碱吸收。HP-β-CyD与盐酸小檗碱混合给药也能促进药物的吸收,但其作用远低于包合作用。结论环糊精的包合作用将有可能成为提高P-糖蛋白底物药物生物利用度的有效手段。     

辛伐他汀大鼠肠吸收动力学研究

目的:研究辛伐他汀在大鼠各肠段的吸收动力学特征。方法:采用大鼠在体肠段回流实验,主要从吸收部位、药物浓度、pH值方面对辛伐他汀的肠段吸收特性进行研究。结果:辛伐他汀在大鼠肠道内无特定吸收部位,各肠段吸收速率常数按十二指肠、结肠、空肠、回肠顺序依次下降,分别为0.03365、0.03190、0.02942、0.02563h-1。辛伐他汀在1.0～20.0μg·mL-1浓度范围内药物吸收量呈线性关系;在pH5.0～7.4内药物吸收不受pH值影响。结论:辛伐他汀在大鼠全肠段均有吸收,吸收符合一级动力学特征,吸收机制为被动扩散,适于制备日服1次缓释给药系统。     

Spray-dried oil-in-water emulsion to improve the intestinal absorption and oral bioavailability of ZLR-8, a nitric oxide-releasing derivative of diclofenac

Objectives Spray‐dried emulsion (SDE) was prepared and characterized to improve the intestinal absorption and oral bioavailability of ZLR‐8, a nitric oxide‐releasing derivative of diclofenac, currently under preclinical development. Methods The intestinal absorption of ZLR‐8 was characterized by single pass intestinal perfusion technique to obtain its absorption and permeability parameters. SDE of ZLR‐8 was prepared and characterized by particle size measurements and in‐vitro release study. Accurate and precise RP‐HPLC methods for the detection of ZLR‐8 and its metabolite diclofenac were constructed to perform the bioavailability study. Key findings It was demonstrated that ZLR‐8 was absorbed in the whole intestine, of which the duodenum segment exhibited the largest absorption ability. ZLR‐8 can be classified into BCS Class 2. SDE significantly enhanced the intestinal absorption rate of ZLR‐8 in duodenum and jejunum but had indistinctive effect on permeability. All concentrations of ZLR‐8 in rat plasma was lower than the limit of detection. A bicompartment model gave the best fit to the plasma diclofenac concentration–time curves. Calculated on AUC_0–12h, the mean relative bioavailability of SDE was 105.4‐fold that of ZLR‐8 suspension. Conclusions SDE significantly improved the intestinal absorption of ZLR‐8 and resulted in a dramatic improvement in its bioavailability.