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1.
Biol Pharm Bull ; 42(3): 365-372, 2019.
Article in English | MEDLINE | ID: mdl-30828069

ABSTRACT

In this study, rats were fed a high-fat diet containing calcium alginate (Ca-Alg) for 5 weeks to examine the effects of Ca-Alg on lipid metabolism including triglyceride (TG) levels in the blood. We also investigated the mechanism of the TG-reducing effect of Alg in vitro. Rats were randomized into 5 groups: high-fat diet group (14% (w/w) lard, HF); three Ca-Alg-containing diet groups (2.5, 5 or 10% (w/w) Ca-Alg) and a resistant maltodextrin (RMD) diet group as a positive control (with 5% (w/w) RMD). The 10% Ca-Alg group showed a significant reduction of body weight increase from the 7th day. In addition, the increase of TG in blood was significantly suppressed, and the amount of TG excreted in feces was increased. Increase of body fat mass was in the order HF > RMD > Ca-Alg 2.5% > Ca-Alg 5% > Ca-Alg 10%, while the total weight of the extracted fat tissues was significantly reduced in the RMD, 5% and 10% Ca-Alg groups. Hepatic pathology showed clear circular vacuoles apparently representing TG accumulation in the HF group, while fewer vacuoles were seen in the Ca-Alg groups. The results of in vitro experiments indicated that Ca-Alg does not directly inhibit lipase activity, but may suppress absorption of TG by forming non-absorbable macromolecular micelles containing TG. These results suggest that Ca-Alg promotes excretion and suppresses absorption of TG, leading to reduced blood TG levels, and decreased hepatic and total body accumulation of fat. The findings should be helpful for designing future clinical trials.


Subject(s)
Adipose Tissue/metabolism , Alginates/pharmacology , Diet, High-Fat , Lipid Metabolism/drug effects , Triglycerides/blood , Alginates/administration & dosage , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Feces/chemistry , Liver/metabolism , Male , Rats
2.
Biol Pharm Bull ; 41(9): 1362-1366, 2018 Sep 01.
Article in English | MEDLINE | ID: mdl-29973436

ABSTRACT

Calcium alginate (Ca-Alg) is known to suppress the postprandial increase of blood glucose, and therefore may be helpful for preventing lifestyle-related diseases such as diabetes. In this work, we examined the mechanism of this effect. As α-amylase activity and α-glucosidase activity are involved in the digestion of starch, we examined the in vitro inhibitory effect of Ca-Alg on these enzymes. Ca-Alg showed little inhibition of α-amylase, but markedly inhibited α-glucosidase activity. The direct binding affinity of glucose for Ca-Alg was low. Also, Ca-Alg had essentially no effect on the membrane permeability of glucose. Therefore, we considered that the suppression of blood glucose by Ca-Alg is predominantly due to a decrease in the efficiency of starch digestion as a result of inhibition of α-glucosidase, possibly due to increased viscosity of the gastrointestinal contents. Next, we investigated the optimum amount in the diet and the optimum particle size of Ca-Alg for suppressing postprandial blood glucose level in rats orally administered a diet containing starch with various amounts and particle sizes of Ca-Alg. We found that 5% by weight of 270-mesh-pass Ca-Alg was most effective.


Subject(s)
Alginates/administration & dosage , Blood Glucose/drug effects , Blood Glucose/metabolism , Dietary Carbohydrates/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/metabolism , Administration, Oral , Animals , Caco-2 Cells , Dietary Carbohydrates/antagonists & inhibitors , Humans , Male , Postprandial Period/drug effects , Postprandial Period/physiology , Rats , Rats, Wistar
3.
Biol Pharm Bull ; 41(9): 1367-1371, 2018 Sep 01.
Article in English | MEDLINE | ID: mdl-29973437

ABSTRACT

We conducted a prospective, randomized, double-blind, 3-group, 3-phase crossover study to evaluate the effect of calcium alginate (Ca-Alg) on the postprandial increase of blood glucose in 15 healthy adult subjects who were given udon noodles containing or not containing Ca-Alg (5 or 8%). The value of ΔCmax (difference between the maximum (Cmax) and pre-feeding (C0) blood glucose levels) was significantly reduced in both Ca-Alg groups, and the area under the blood glucose level-time curve over 120 min (ΔAUC, with C0 as the baseline) was also significantly reduced. Thus, supplementation of noodles with Ca-Alg significantly suppressed both the peak postprandial blood glucose level and the total amount of glucose absorption. Blood calcium (Ca) concentration was significantly increased at 120 min after ingestion, but there was no marked change of other parameter values. A questionnaire indicated that addition of Ca-Alg did not affect the acceptability of the noodles. These results indicate that Ca-Alg might a useful food additive for helping to prevent lifestyle-related diseases without adversely affecting individual eating habits.


Subject(s)
Alginates/administration & dosage , Blood Glucose/drug effects , Blood Glucose/metabolism , Postprandial Period/drug effects , Starch/administration & dosage , Adult , Cross-Over Studies , Dietary Carbohydrates/administration & dosage , Double-Blind Method , Female , Flour , Humans , Male , Postprandial Period/physiology , Prospective Studies , Surveys and Questionnaires , Young Adult
4.
Biol Pharm Bull ; 40(7): 967-974, 2017.
Article in English | MEDLINE | ID: mdl-28674261

ABSTRACT

Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). After 2 d exposure of hepatocyte spheroids to omeprazole, phenobarbital and rifampicin (typical inducers of CYP1A2, 2B6 and 3A4, respectively), CYP1A2, 2B6 and 3A4 mRNA expression levels were significantly increased. The mRNA induction of CYP2B6 remained reasonably stable between days 2 and 14 of exposure to inducers, while induction of both CYP1A2 and 3A4 continued to increase up to day 14. These enzyme activities were all significantly increased compared with the control until day 14. Our findings indicate that our 3D hepatocyte spheroids system would be especially suitable for long-term testing of enzyme activity induction by drugs, either to predict or to verify clinical events.


Subject(s)
Hepatocytes/metabolism , Pharmaceutical Preparations/metabolism , 3T3 Cells , Animals , Cells, Cultured , Chemical and Drug Induced Liver Injury , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/metabolism , Enzyme Induction , Hepatocytes/cytology , Humans , Mice
5.
J Toxicol Sci ; 42(4): 499-507, 2017.
Article in English | MEDLINE | ID: mdl-28717109

ABSTRACT

We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured. The cumulative AST, LDH or γ-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for γ-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F1.2), no consistent difference between Sph(f+) and Sph(f-) was found, although several F1.2 values were undetermined, especially in Sph(f+). The IC50 of albumin secretion and F1.2 of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Chlorpromazine/toxicity , Diclofenac/toxicity , Flutamide/toxicity , Hepatocytes/cytology , Isoniazid/toxicity , Spheroids, Cellular , Toxicity Tests/methods , Alanine Transaminase/metabolism , Albumins/metabolism , Aspartate Aminotransferases/metabolism , Cells, Cultured , Feeder Cells , Humans , L-Lactate Dehydrogenase/metabolism , Liver/drug effects , Liver/enzymology , Liver/metabolism , Time Factors , gamma-Glutamyltransferase/metabolism
6.
Biol Pharm Bull ; 39(11): 1893-1896, 2016.
Article in English | MEDLINE | ID: mdl-27803462

ABSTRACT

We investigated the relationship between the physical parameters of various metal ions, including toxic metal ions, and the binding affinity of these metal ions for alginate (Alg). The binding constant, K, of Sr2+ was the highest among all tested metal ions. The order of K values was: Sr2+>Pb2+>Tb3+>Dy3+>Ca2+>Cd2+>Mg2+>Fe2+>Fe3+>Co2+>Al3+>Ni2+>Cs+>Cu2+>Ag+>Li+>K+. The metal ions showing the highest K values had ionic radii within the range of about 90-120 pm. Moreover, the K values of divalent or trivalent metal ions tended to be higher than those of monovalent ions. The number of binding sites per 1 mg of Alg (n) was highest for K+, followed by Pb2+ and Cs+. The order of affinity (calculated as the product of n and K) was Pb2+>Dy3+>Tb3+>Sr2+>Ca2+>Mg2+>Cd2+>Fe2+, Fe3+>Cs+>Al3+>Co2+>Ni2+>Cu2+>Ag+>K+>Li+. Our results support the idea that Alg would be effective as an excretion accelerator and/or absorption inhibitor for various toxic metal ions.


Subject(s)
Alginates/chemistry , Metals/chemistry , Binding Sites , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Sequestering Agents/chemistry
7.
J Pharm Sci ; 105(1): 339-42, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26852864

ABSTRACT

We investigated the influence of sweet and umami (savory) tastants on the intestinal absorption of cephalexin (CEX), a substrate of peptide transporter 1 (PEPT1, SLC15A1) in rats. After oral administration of glucose or mannitol to rats, CEX was administered together with a second dose of glucose or mannitol. Western blot analysis indicated that expression of PEPT1 in rat jejunum membrane was decreased by glucose, compared to mannitol. Furthermore, the maximum plasma concentration (Cmax) of orally administered CEX was reduced by glucose compared to mannitol. The effect of glucose was diminished by nifedipine, a L-type Ca(2+) channel blocker. We also found that Cmax of orally administered CEX was reduced by treatment with L-glutamic acid, compared to D-glutamic acid. Thus, excessive intake of glucose and L-glutamic acid may impair oral absorption of PEPT1 substrates.


Subject(s)
Glucose/pharmacology , Glutamic Acid/pharmacology , Sensory Receptor Cells/drug effects , Symporters/metabolism , Taste Buds/drug effects , Animals , Calcium Channel Blockers/pharmacology , Cephalexin/pharmacokinetics , Intestinal Absorption , Jejunum/drug effects , Jejunum/metabolism , Male , Mannitol/pharmacology , Membranes/drug effects , Membranes/metabolism , Nifedipine/pharmacology , Peptide Transporter 1 , Protein Transport/drug effects , Rats , Rats, Wistar , Symporters/drug effects
8.
Biol Pharm Bull ; 39(1): 62-7, 2016.
Article in English | MEDLINE | ID: mdl-26725428

ABSTRACT

We examined whether calcium alginate (Ca-Alg) reduces blood cholesterol levels in rats fed a high-cholesterol diet. First, we examined taurocholate adsorption in vitro by various types of sodium alginate (Na-Alg). High molecular-weight, guluronic acid-rich Na-Alg showed the greatest adsorption of taurocholate, and therefore the corresponding Ca-Alg was chosen for the in vivo study. Rats were fed a high-cholesterol diet or a Ca-Alg-containing diet for 2 weeks. Body weight and diet intake were measured, and the general condition of the animals was monitored during this period. After 14 d, the plasma concentration of cholesterol, portal plasma concentration of bile acid, and bile acid in feces were measured. The plasma concentration of cholesterol was significantly reduced in rats fed a 2% Ca-Alg-containing diet. Furthermore, the portal concentration of bile acid was significantly lowered in the 2% Ca-Alg group. A tendency for a Ca-Alg concentration-dependent increase in fecal excretion of bile acid was also seen, although it was not statistically significant. While several changes in biochemical parameters and histopathological findings were observed, all the values remained within the physiological range. These results indicate that Ca-Alg is effective in reducing plasma cholesterol. A possible mechanism would be enhanced fecal excretion of bile acid due to reduced intestinal reabsorption, which in turn might stimulate bile acid synthesis from cholesterol in the liver, leading to a decrease in plasma cholesterol.


Subject(s)
Alginates/therapeutic use , Cholesterol/blood , Hypercholesterolemia/drug therapy , Hypolipidemic Agents/therapeutic use , Alginates/administration & dosage , Alginates/pharmacology , Animals , Dietary Fats/administration & dosage , Dietary Fats/adverse effects , Dose-Response Relationship, Drug , Epichlorohydrin/therapeutic use , Glucuronic Acid/administration & dosage , Glucuronic Acid/pharmacology , Glucuronic Acid/therapeutic use , Hexuronic Acids/administration & dosage , Hexuronic Acids/pharmacology , Hexuronic Acids/therapeutic use , Hypercholesterolemia/blood , Hypercholesterolemia/chemically induced , Hypolipidemic Agents/administration & dosage , Imidazoles/therapeutic use , Lipid Metabolism , Male , Random Allocation , Rats , Rats, Wistar , Resins, Synthetic/therapeutic use , Specific Pathogen-Free Organisms
9.
Biopharm Drug Dispos ; 37(1): 39-45, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26590007

ABSTRACT

The study investigated whether quinolone antibiotics inhibit the PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited the uptake of PEPT1 substrate phenylalanine-Ψ(CN-S)-alanine (Phe-Ψ-Ala) in HeLa/PEPT1 cells to 31.6 ± 1.3%, 27.6 ± 2.9%, 36.8 ± 2.2% and 32.6 ± 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 ± 1.29 mm. In addition, MFLX significantly decreased the cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (C(max)) of orally administered Phe-Ψ-Ala was significantly decreased in the presence of MFLX (171 ± 1 ng/ml) compared with that in its absence (244 ± 9 ng/ml). The area under the concentration-time curve (AUC) of orally administered Phe-Ψ-Ala in the presence of MFLX (338 ± 50 ng/ml · h) tended to decrease compared with that in its absence (399 ± 75 ng/ml · h). The oral bioavailability of Phe-Ψ-Ala in the presence and absence of MFLX was 41.7 ± 6.2% and 49.2 ± 9.2%, respectively. The results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction.


Subject(s)
Anti-Bacterial Agents/pharmacology , Phenylalanine/pharmacokinetics , Quinolones/pharmacology , Symporters/metabolism , Administration, Oral , Animals , Drug Interactions , HeLa Cells , Humans , Intestinal Absorption , Male , Peptide Transporter 1 , Peptides/pharmacokinetics , Phenylalanine/blood , Rats, Wistar , Symporters/antagonists & inhibitors
10.
Biol Pharm Bull ; 37(4): 604-7, 2014.
Article in English | MEDLINE | ID: mdl-24694606

ABSTRACT

We found that bacteria in a commercial soil conditioner sold in Ishinomaki, Miyagi, exhibited concentrative and saturable cesium ion (Cs(+)) uptake in the natural range of pH and temperature. The concentration of intracellular Cs(+) could be condensed at least a few times higher compared with the outside medium of the cells. This uptake appeared to be mediated by a K(+) transport system, since Cs(+) uptake was dose-dependently inhibited by potassium ion (K(+)). Eadie-Hofstee plot analysis indicated that the Cs(+) uptake involved a single saturable process. The maximum uptake amount (Jmax) was the same in the presence and absence of K(+), suggesting that Cs(+) and K(+) uptakes were competitive with respect to each other. These bacteria might be useful for bioremediation of cesium-contaminated soil.


Subject(s)
Bacteria/metabolism , Cesium/metabolism , Potassium/metabolism , Soil Pollutants/metabolism , Biological Transport/drug effects , Dose-Response Relationship, Drug , Hydrogen-Ion Concentration , Potassium/pharmacology , Temperature , Time Factors
11.
Drug Metab Pharmacokinet ; 29(3): 254-8, 2014.
Article in English | MEDLINE | ID: mdl-24366438

ABSTRACT

Cilnidipine is reported to show antihypertensive and neuroprotective actions in a rat brain ischemia model, but is barely distributed to normal brain, suggesting that its uptake into normal brain is inhibited by efflux transporter(s), such as P-glycoprotein (P-gp). Here, we investigated whether P-gp regulates the brain distribution of cilnidipine. Intracellular accumulation of cilnidipine was decreased in P-gp-overexpressing porcine kidney epithelial cells (LLC-GA5-COL150 cells) compared with control LLC-PK1 cells and the decrease was markedly inhibited by verapamil, a P-gp inhibitor. Further, cilnidipine concentration in the brain of P-gp knockout mice was significantly increased after cilnidipine administration, compared with that in wild-type mice. Moreover, when cilnidipine was administered to male spontaneously hypertensive rats (SHR) with tandem occlusion of the distal middle cerebral and ipsilateral common carotid artery, its concentration in the ischemic hemisphere was 1.6-fold higher than that in the contralateral hemisphere. This result was supported by visualization of cilnidipine distribution using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry (MALDI-TOF/MS) imaging. Our results indicated that cilnidipine is normally excluded from the brain by P-gp-mediated efflux transport, but P-gp function is impaired in ischemic brain and consequently cilnidipine is distributed to the ischemic region.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Brain Ischemia/metabolism , Brain/metabolism , Dihydropyridines/metabolism , Animals , Carotid Arteries/metabolism , Cell Line , LLC-PK1 Cells , Male , Mice , Middle Cerebral Artery/metabolism , Rats , Rats, Inbred SHR , Swine
12.
Biol Pharm Bull ; 36(3): 485-91, 2013.
Article in English | MEDLINE | ID: mdl-23318531

ABSTRACT

Alginate (ALA), which is an intercellular polysaccharide associated with brown algae, is used as a food additive, a health food and a medicine. Here, we first examined the adsorption of strontium (Sr) and cesium (Cs) by ALA in vitro, and then evaluated the effects of ALA on absorption and excretion of Sr and Cs in rats, in order to evaluate its potential usefulness for minimizing radiation damage from materials released after a nuclear accident. Both Sr and Cs were concentration-dependently adsorbed by sodium alginate (ALA-Na) in vitro. In rats given diet containing either ALA-Na or calcium alginate (ALA-Ca) for two weeks, the plasma concentration of Sr gradually decreased compared with the controls (normal diet); however, in the case of Cs, the plasma concentration was decreased only in the ALA-Ca group, but not the ALA-Na group. Moreover, we examined the effect of preadministration of diet containing either ALA-Na or ALA-Ca on absorption of Sr and Cs administered orally as the chloride salts to rats. Absorption of both Sr and Cs was reduced in the ALA-Ca group, while absorption of only Sr was reduced in the ALA-Na group. Safety assessments indicated that ALA-Ca is safer than ALA-Na. These results indicate that ALA-Ca reduces absorption and promotes excretion of both Sr and Cs, while ALA-Na does so only for Sr.


Subject(s)
Alginates/pharmacology , Cesium/pharmacokinetics , Strontium/pharmacokinetics , Absorption , Alginates/toxicity , Animals , Dose-Response Relationship, Drug , Glucuronic Acid/pharmacology , Glucuronic Acid/toxicity , Hexuronic Acids/pharmacology , Hexuronic Acids/toxicity , Male , Rats , Rats, Wistar
13.
Drug Metab Pharmacokinet ; 28(2): 98-103, 2013.
Article in English | MEDLINE | ID: mdl-22850759

ABSTRACT

  Conflicting results have been reported on segmental differences in expression of P-glycoprotein (P-gp) along the small intestine of animals and humans. In this study, we investigated P-gp mRNA and protein levels within each of nine segments of rat small intestine. In addition, P-gp activity in each segment was evaluated in terms of permeability of rhodamine123 (Rho123), a typical P-gp substrate, using the serial intestinal non-everted sac method. The P-gp mRNA levels tended to increase from the duodenum to the ileum, with peaks in the upper and lower ileum, while P-gp protein level reached its maximum in the middle ileum. The activity of P-gp was also the highest in the middle ileum, and was highly correlated with P-gp protein level. The double-peaked plasma concentration profile that was observed following oral administration of Rho123 to rats could be well reproduced by an intestinal compartmental kinetic model incorporating inter-segmental differences of absorption and excretion rate constants. Our results suggest that the heterogeneous distribution of P-gp along the small intestine plays a key role in causing the double-peak of plasma concentration of P-gp substrates following oral administration to rats.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Intestinal Absorption , Intestine, Small/metabolism , Rhodamine 123/blood , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Administration, Oral , Animals , Duodenum/metabolism , Ileum/metabolism , Male , Models, Biological , Rats , Rhodamine 123/administration & dosage , Rhodamine 123/metabolism
14.
Drug Metab Pharmacokinet ; 21(5): 424-8, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17072096

ABSTRACT

The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Intestinal Absorption/drug effects , Rhodamine 123/pharmacokinetics , Tartrates/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacokinetics , Biological Transport/drug effects , Biological Transport/physiology , Blotting, Western , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/pharmacokinetics , Colon/cytology , Colon/drug effects , Colon/metabolism , Daunorubicin/administration & dosage , Daunorubicin/pharmacokinetics , Diffusion Chambers, Culture/methods , Fluorescent Dyes/pharmacokinetics , Ileum/cytology , Ileum/drug effects , Ileum/metabolism , Injections, Intravenous , Jejunum/cytology , Jejunum/drug effects , Jejunum/metabolism , Male , Rats , Rats, Wistar , Verapamil/administration & dosage , Verapamil/pharmacokinetics
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