The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier

The reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) are ubiquitously expressed in normal and malignant mammalian tissues and in human solid tumor cell lines. This article addresses the extent to which PCFT contributes to transport of pemetrexed and to the activities of this and other antifolates relative to RFC at physiological pH. Either RFC or PCFT cDNA was stably transfected into a transporter-null HeLa cell variant to achieve activities similar to their endogenous function in wild-type HeLa cells. PCFT and RFC produced comparable increases in pemetrexed activity in growth medium with 5-formyltetrahydrofolate. However, PCFT had little or no effect on the activities of methotrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxyquinazolin-6-ylmethyl)-N-methyl-amino]-2-thenoyl)-l-glutamic acid (raltitrexed, Tomudex; ZD1694), or N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-l-ornithine (PT523) in comparison with RFC irrespective of the folate growth source. PCFT, expressed at high levels in Xenopus laevis oocytes and in transporter-competent HepG2 cells, exhibited a high affinity for pemetrexed, with an influx K(m) value of 0.2 to 0.8 muM at pH 5.5. PCFT increased the growth inhibitory activity of pemetrexed, but not that of the other antifolates in HepG2 cells grown with 5-formyltetrahydrofolate at physiological pH. These findings illustrate the unique role that PCFT plays in the transport and pharmacological activity of pemetrexed. Because of the ubiquitous expression of PCFT in human tumors, and the ability of PCFT to sustain pemetrexed activity even in the absence of RFC, tumor cells are unlikely to become resistant to pemetrexed as a result of impaired transport because of the redundancy of these genetically distinct routes.     

Involvement of reduced folate carrier 1 in the inner blood-retinal barrier transport of methyltetrahydrofolate

The purpose of this study was to elucidate the mechanism of methyltetrahydrofolate (MTF) transport at the inner blood-retinal barrier (inner BRB). The characteristics and function of MTF transport at the inner BRB were examined using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB. The [3H]MTF uptake by TR-iBRB2 cells increased with lowering extracellular pH and was Na+- and Cl--independent. The [3H]MTF uptake was concentration-dependent with a K(m) of 5.1 microM. This process was inhibited by reduced folate carrier 1 (RFC1) substrates, such as methotrexate and formyltetrahydrofolate, in a concentration-dependent manner with an IC50 of 8.7 and 2.8 microM, respectively, suggesting that RFC1 mediates MTF uptake in TR-iBRB2 cells. Although both RFC1 and proton-coupled folate transporter (PCFT) mRNA, which are pH-sensitive folate transporters, are expressed in TR-iBRB2 cells and isolated rat retinal vascular endothelial cells, the expression level of RFC1 mRNA was 83- and 49-fold greater than that of PCFT, respectively. Taken together, the above findings are consistent with the involvement of RFC1 in the inner BRB transport of MTF.     

Molecular and functional characteristics of proton-coupled folate transporter

Proton-coupled folate transporter (PCFT) has recently been identified as the molecular entity of the carrier-mediated intestinal folate transport system. PCFT has been demonstrated to be most abundantly expressed in the upper small intestine, localizing at the brush border membrane of epithelial cells, transport folate and its analogs more efficiently at lower (acidic) pH by a H(+)-coupled cotransport mechanism, and have a high affinity for folate with a Michaelis constant (K(m)) of a few microM at pH 5.5 and somewhat lower affinities for reduced folates and methotrexate (MTX). A loss of PCFT function due to a homozygous mutation in its gene has been indicated to be responsible for hereditary folate malabsorption. Thus, PCFT has all the characteristics of the brush border H(+)-coupled cotransporter for folate and analogs, which has long been suggested to be present in the intestine. Furthermore, sulfasalazine was found to be a potent inhibitor of PCFT, suggesting that it is a risk factor that would cause malabsorption of folate and also MTX, when coadministered in the treatment of rheumatoid arthritis. Understanding the molecular and functional characteristics of PCFT should be important and helpful in exploring therapeutic strategies for folate malabsorption and in optimizing therapies using antifolate drugs.     

Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes

The small intestine is the major site of drug absorption. Some reports in the literature have evoked the concept of “absorption windows” in the small intestine: are there specific regions where drug absorption is significantly higher than others? To investigate this question, we used an everted gut sac method to study the permeability of drugs and markers every 3–4 cm down the entire small intestine in rat. These markers were chosen to be representative of the mechanisms by which drugs cross the small intestinal mucosa: paracellular and transcellular passive diffusion, via influx transporters, and a drug (digoxin) that is effluxed from cells by P-glycoprotein (P-gp). The passive diffusion and influx transporter markers gave similar profiles with a plateau of permeability along the jejunum, and with the exception of L-Dopa, lower permeability in the ileum. Digoxin showed a linear decrease in the profile from the proximal jejunum to the ileum. Permeability in the duodenum was two to three times lower than the jejunum for all compounds. There were no narrow specific regions of high permeability and so the concept of discrete “absorption windows” along the small intestine as suggested from some pharmacokinetic studies may be related to other effects such as pH and/or solubility.     

5‐Fluorouracil treatment alters the expression of intestinal transporters in rats

5‐Fluorouracil (5‐FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5‐FU‐induced intestinal damage on the expression of intestinal transporters: P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5‐FU (30 mg/kg/day, p.o. ) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real‐time PCR and Western blotting, respectively. In the 5‐FU‐treated rats, the protein levels of P‐gp and Bcrp in the upper segment were significantly increased to 15‐ and 2.6‐fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5‐FU in almost all segments. A remarkable increase in P‐gp expression was shown, the uptake of digoxin, a P‐gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5‐FU‐treated rats was decreased compared with that of the control. In conclusion, 5‐FU‐induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5‐FU‐induced intestinal damage may affect transporter‐mediated drug absorption of orally administered drugs in the clinical setting.     

Protective effect of a synthetic analog of prostaglandin E(1) on the small intestinal damage induced by the administration of methotrexate to rats

Antitumor drugs like methotrexate cause damage to the small intestine, resulting in malabsorption. The present study evaluated this damage by determining the small intestinal absorption of 3-O-methyl-D-glucose (3-OMG) and a poorly absorbable marker, fluorescein isothiocyanate-labeled dextran (FD-4; average molecular mass, 4.4 KDa) using the in vitro everted intestine and in situ intestinal loop techniques. Methotrexate (15 mg/kg body weight) was orally administered to rats once daily for 5 days. A synthetic analog of prostaglandin E(1), OP-1206 (17S,20-dimethyl-trans-Delta(2)-prostaglandin E(1); 0.5 microg/kg body weight) was orally administered to rats twice a day for 5 days. The absorption clearance of FD-4 via the small intestine of the methotrexate-treated rats increased marked, but that of the methotrexate- and OP-1206-treated rats was significantly lower than that of the rats treated only with methotrexate. The absorption clearance of [(3)H]-3-OMG via the small intestine of the methotrexate-treated rats fell markedly, but that of the methotrexate- and OP-1206-treated rats was significantly greater than that of the rats treated only with methotrexate. The changes in AUC values of FD-4 and [(3)H]-3-OMG obtained from in situ intestinal loop experiment showed the same trends as those seen in the absorption clearance from the in vitro everted intestine experiment. These results show that OP-1206 alleviates the methotrexate-induced damage to the small intestine of rats.     

Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats

The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.     

Expression of clinically relevant drug‐metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra‐subject analysis

The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug‐drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug‐metabolizing enzymes (CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT1A, UGT1A, UGT2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real‐time RT‐PCR. Enzyme expression was correlated with expression data of the nuclear receptors PXR, CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, SULT1A, UGT1A and UGT2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP3A4, CYP2C9, SULT1A and UGT1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site‐dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine.     

Characterization of folate transport mediated by a low pH route in mouse L1210 leukemia cells with defective reduced folate carrier function

Folate influx at low pH was characterized in MTXrA cells, an L1210 mouse leukemia cell line with a functional defect in the reduced folate carrier. Folic acid influx in MTXrA cells was negligible at pH 7.5, increased 13-fold as the pH was decreased to 6.0, and was indistinguishable from that in L1210 cells. In contrast, while methotrexate (MTX) influx in MTXrA cells at pH 6.0 was 15-fold higher than at pH 7.5, in L1210 cells it was decreased by half. Influx of MTX, folic acid, 5-methyltetrahydrofolate and 5-formyltetrahydrofolate in MTXrA cells was increased at pH < 7.0, but their pH optima and profile differed substantially. Influx of MTX and 5-methyltetrahydrofolate at pH 6.0 showed saturability, with a Kt of 2.65 and 0.56 microM, and a Vmax of 0.45 and 0.083 nmol/g dry wt/min, respectively. MTX influx mediated by the low pH transporter was insensitive to the anionic composition of the transport buffer and affected minimally (approximately 20%) by Na+ substitution. The anion transport inhibitors sulfobromophthalein, diisothiocyanatostilbene disulfonic acid, and acetamidoisothiocyanatostilbene disulfonic acid were not effective inhibitors of the low pH route. MTX transport at low pH did not increase in MTXrA-R16 cells, an MTXrA derivative with 10-fold overexpression of the reduced folate carrier (RFC) due to transfection with RFC1 cDNA. Inhibition of reduced folate carrier activity with acetamidoisothiocyanatostilbene disulfonic acid resulted in identical MTX influx in L1210, MTXrA, and MTXrA-R16 cells at pH 5.5. Finally, low pH-mediated MTX influx was reduced by energy inhibitors and partially inhibited by ionophores (nigericin > monensin > valinomycin). The data indicate that L1210 and MTXrA cells express similar activities of a low pH folate transporter that has properties distinct from, and independent of, the reduced folate carrier.     

Protective effect of prostaglandins on the methotrexate induced damage of small intestine in rats

Methotrexate (MTX) treatment causes the damage of the small intestine, resulting in malabsorption. The aim of this study was to investigate the effect of prostaglandins (PGs), prostaglandin E1 (PGE1) and prostaglandin I2 (PGI2) analogues, on the MTX-induced damage of rat small intestine by examining the permeability of the small intestinal epithelium. The rats were treated as follows: MTX (15 mg/kg/day), MTX and PGE1/PGI2 analogues (0.5 and 5 micrograms/kg/twice a day), PGE1/PGI2 analogues alone, and sterile saline (control). All drugs were given orally for 5 days. The intestinal permeability of fluorescein isothiocyanate labeled dextran with average molecular mass 4.4 KDa (FD-4) was examined to evaluate the dysfunction of the small intestine by the in vitro everted small intestine technique. The permeation clearance of FD-4 obtained from the in vitro experiment of the MTX-treated rats increased remarkably, but that of the MTX and PGE1/PGI2 analogue-treated rats was significantly lower than that of the MTX-treated rats. These results indicated that PGE1 or PGI2 analogues possibly alleviated the MTX-induced damage of the small intestine of rats.     

Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs

The intestinal absorptive characteristics and the efflux mechanisms of 9-nitrocamptothecin (9-NC), a novel water-insoluble camptothecin (CPT) derivative, were investigated. The Caco-2 cells and the everted gut sacs were used as models of the intestinal mucosa to assess transepithelial transport of 9-NC. The determination of 9-NC was performed by HPLC. In the Caco-2 cells, the absorptive transport of 9-NC was pH dependent and the transport was enhanced at weakly acidic pH on the apical side. No concentration dependence and saturation were observed for the absorptive transport of 9-NC at concentrations up to 250 microM, while secretory transport were concentration dependent and saturable process (K(m) was 49.8 +/- 1.2 microM, V(max) was 38.28 +/- 0.8 ng/cm(2)/min). In the presence of verapamil (100 microM) and CsA (10 microM), potent inhibitors of P-glyprotein (P-gp)/MRP2 (cMOAT), the P(appBL-AP)/P(appAP-BL) ratio was decreased from 3.4 to 1.4 and 1.3, respectively, and permeation of apical to basolateral was enhanced approximately two-fold. In the everted gut sacs, the absorption of 9-NC was passive diffusion and had no significant difference in different gut regions. Adding verapamil in the everted gut sacs over a concentration ranging from 10 to 100 microM, the absorption of 9-NC was significantly enhanced, especially more markedly in lower small intestine (P < 0.05). Overall, the current study suggests that pH and efflux transporters are capable of mediating the absorption and efflux of 9-NC, and they may play significant roles in limiting the oral absorption of 9-NC.     

Transport characteristics of candesartan in human intestinal Caco‐2 cell line

The intestinal absorptive characteristics and the efflux mechanisms of candesartan (CDS), a novel angiotensin II type 1 receptor blocker, were investigated. The Caco‐2 cells were used as models of the intestinal mucosa to assess uptake and transport of CDS. The determination of CDS was performed by HPLC‐Flu. In the Caco‐2 cells, the uptake and absorptive transport of CDS were pH‐independent (in the pH range 6.0–8.0). Passive membrane diffusion dominates the absorptive transport behavior of CDS across Caco‐2 cells, while secretory transport was a concentration‐dependent and saturable process. In the presence of cyclosporin A and verapamil, potent inhibitors of P‐glycoprotein (P‐gp), the P_ratio decreased from 3.8 to 2.3 and 1.8, respectively, and permeation of apical to basolateral was enhanced. Overall, the current study suggests that efflux transporters are capable of mediating the absorption and secretion of CDS, and they may play significant roles in limiting the oral absorption of CDS. Copyright © 2009 John Wiley & Sons, Ltd.     

Monoketocholate can decrease transcellular permeation of methotrexate across Caco‐2 cell monolayers and reduce its intestinal absorption in rat

Objectives Bile salts have been shown to decrease the absorption of methotrexate in the rat intestine by an unknown mechanism. We aimed to examine this effect. Methods We assessed apical‐to‐basolateral (AP‐BL) permeation of methotrexate (5 μM) across Caco‐2 cell monolayers pretreated with various concentrations (0, 0.25, 0.5, 1, 3 and 5 mm ) of sodium cholate or its semisynthetic analogue, sodium 12‐monoketocholate. We also determined the effect of orally administered 12‐monoketocholate on the intestinal absorption of methotrexate in rats to evaluate a possible in‐vitro–in‐vivo correlation. Key findings It was found that sodium cholate and sodium 12‐monoketocholate decreased the AP‐BL permeation of methotrexate at low concentrations (maximal inhibition at 0.25 and 1 mm , respectively) and increased it at higher concentrations. Determination of [¹⁴C] mannitol permeation and electrical resistance of monolayers during experiments showed that membrane integrity was not compromised at low concentrations of bile salts but was disrupted at higher concentrations. Subsequently, we examined the effect of the simultaneous oral administration of sodium 12‐monoketocholate (4, 20, 40 and 80 mg/kg) on the intestinal absorption of methotrexate in rats after an oral dose (5 mg/kg). The pharmacokinetic study showed that 12‐monoketocholate at 4 and 20 mg/kg did not change the methotrexate area under the serum concentration–time curve whereas sodium 12‐monoketocholate at 40 and 80 mg/kg significantly reduced it. Conclusions Sodium 12‐monoketocholate appears to decrease the intestinal absorption of methotrexate in rats by inhibition of transcellular active transport.     

Gastrointestinal absorption of inorganic mercuric compounds in vitro

Effects of intraluminal pH on the intestinal absorption and tissue binding of HgCl2 and HgO were studied in the everted sac of rat small intestine. The sac was incubated in media containing HgCl2 or HgO (10(-5 M] at different pH values. With an increase in pH, the uptake of HgCl2 in the intestinal tissue decreased and the transport of HgCl2 through the tissue increased. Similar pH dependence was observed in the uptake of HgO. The transport of HgCl2 seemed to be correlated with mercury bound to a protein (molecular weight between 440,000 and 669,000) and to be inversely correlated with that bound to intestinal metallothionein. These results suggest that the increase of intraluminal pH promotes the absorption of HgCl2 accompanied by a change in the binding of HgCl2 to the everted tissue sac.     

Decreased Activity and Expression of Intestinal Oligopeptide Transporter PEPT1 in Rats with Hyperthyroidism in Vivo

PURPOSE: To examine the effect of thyroid hormone status on PEPT1 in vivo, the activity and expression of PEPT1 in the small intestine were examined in euthyroid and hyperthyroid rats. METHODS: Hyperthyroidism was induced by treating rats with L-thyroxine (12 mg/L) in the drinking water for 21 days. Transport activity was measured by everted small intestinal preparations and in situ intestinal loop technique. Expressions of PEPT1 mRNA and protein were evaluated by competitive polymerase chain reaction and Western blotting, respectively. RESULTS: The uptake of [14C]glycylsarcosine by everted small intestinal preparations was significantly decreased in hyperthyroid rats, whereas that of methyl-alpha-D-[14C(U)]-glucopyranoside was not altered. Kinetic analysis showed that the Vmax value for [14C]glycylsarcosine uptake was significantly decreased in hyperthyroid rats, whereas the Km value was not affected. The mean portal vein concentrations after intrajejunal administration of [14C]glycylsarcosine were also decreased in hyperthyroid rats. Moreover, hyperthyroidism caused a significant decrease in the expression of PEPT1 mRNA in the small intestine, whereas the expression of Na+/glucose cotransporter (SGLT1) mRNA was not changed. The level of PEPT1 protein was also decreased in the small intestine of hyperthyroid rats. CONCLUSIONS: These results indicate that in hyperthyroid rats, the activity and expression of PEPT1 were decreased in the small intestine.     

Possible factors behind the enhanced gastrointestinal absorption of griseofulvin from liquid organic acid ester solutions in rats

Some possible factors involved in the enhanced gastrointestinal absorption of griseofulvin from ethyl acetoacetate, methyl propionate and methyl caproate solutions were investigated. The participation of lymphatic absorption to the enhanced griseofulvin was ruled out from findings that the ratio of lymphatic absorption to total systemic absorption was only 0.28%. The effect of esters on the intestinal membrane permeability was investigated employing in vitro rat everted intestine and in situ intestinal perfusion techniques. The transfer rate of griseofulvin from each vehicle across the everted intestine was increased in the following order: aqueous suspension ethyl acetoacetate methyl caproate methyl propionate. This order was coincident with the order of their absorption-enhancing potencies observed in vivo and a linear relationship was obtained between the transfer rate of griseofulvin from each vehicle in vitro and the value of the AUC or C_max obtained after intraduodenal administration. An increase in the exsorption rate of griseofulvin from blood vessel into small intestinal lumen was also observed in the presence of esters in the lumen aqueous perfusate. These results suggest that the enhanced intestinal absorption of griseofulvin from organic acid ester solution is mainly due to the increased membrane permeability caused by esters. The increased membrane permeability caused by methyl propionate and methyl caproate was also observed when phenolsulfonphthalein was used instead of griseofulvin.     

托美丁在大鼠肠道的吸收动力学

目的:研究托美丁在大鼠各肠段的吸收动力学特征。方法:采用大鼠离体肠外翻模型,用HPLC法对托美丁进行检测,计算托美丁在肠道的吸收参数。结果:托美丁在全肠段均有良好吸收,吸收速率按空肠、十二指肠、结肠、回肠的顺序依次下降,吸收速率常数依次为0.292 8,0.214 5,0.186 9,0.080 9 h-1。结论:托美丁在大鼠整个肠段的吸收呈现一级动力学特征,吸收机制为被动扩散。     

外翻肠囊法研究奥硝唑对映体在大鼠不同肠段的吸收特性

目的考察奥硝唑在大鼠各肠段的吸收特性及奥硝唑两手性对映体在大鼠不同肠段吸收的差异性。方法采用大鼠外翻肠囊法,以HPLC手性色谱柱法测定奥硝唑在不同肠段的吸收量以及S-奥硝唑及R-奥硝唑的同一肠段肠吸收量,并分别计算吸收速率常数(Ka)和表观渗透系数(P_(app)),同法考察了P-蛋白抑制剂(维拉帕米和环孢素A)对奥硝唑肠吸收特性的影响。结果奥硝唑在不同肠段吸收均呈线性,符合零级药物吸收速率,吸收趋势为空肠>回肠>结肠。在空肠段两对映体以近于1∶1的比例同时吸收,吸收速率不存在显著差异,随着供试液中奥硝唑质量浓度的上升,Ka呈线性增加(R~2>0.99),Paap基本保持不变,P-蛋白抑制剂对奥硝唑的肠吸收没有显著性影响(P>0.05)。结论奥硝唑在不同肠段的吸收有差异,空肠部位是吸收的最佳部位(P<0.05),S-奥硝唑与R-奥硝唑在肠道中吸收速率不存在显著差异,吸收以被动扩散机制为主,奥硝唑不是P-糖蛋白的底物。     

5-氟尿嘧啶口服微乳的制备及其大鼠肠吸收作用研究

目的:制备5-氟尿嘧啶(5-Fu)口服微乳,并考察其在大鼠肠吸收的作用。方法:以肉豆蔻酸异丙酯为油相、单辛/癸酸甘油酯为乳化剂,借助伪三元相图法对不同5-Fu微乳处方进行评价;用外翻肠囊法制备肠吸收离体模型,考察5-Fu微乳的吸收部位和促吸收效果。结果:选择肉豆蔻酸异丙酯-单辛/癸酸甘油酯-无水乙醇-水(Km=1∶2)体系作为5-Fu微乳的载药体系;与其溶液比较,5-Fu微乳可明显改善药物的肠吸收,小肠中后段是其最佳吸收部位,90min时累积吸收率微乳是溶液的3倍。结论:所制备的5-Fu微乳性质稳定、肠吸收效果良好。