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Biomedical subjects

M G Lee

Publications and source records attributed to M G Lee.

At least 37 records · Page 2Linked to original sources
PubMed2001

Prevention of c-Jun/activator protein-1 activation and microsomal epoxide hydrolase induction in the rat liver by cysteine during protein-calorie malnutrition.

Protein-calorie malnutrition (PCM), a major global health problem, arises during protein and/or energy deficit due to disease and nutritional inadequacy. To date, cellular adaptive responses and gene expression associated with PCM remain poorly understood. In view of the primary role of the liver in energy conversion, the present study was designed to investigate changes in hepatic morphology and molecular alterations during PCM. PCM caused marked decreases in the cytoplasmic eosinophilic content and nuclear shrinkage in the hepatocytes with a decrease in glutathione content. The nuclear activator protein-1 (AP-1) complex was activated in the liver of PCM rats. AP-1-binding activity of nuclear extracts produced from PCM rats was reduced by the presence of anti-c-Jun antibody. Microsomal epoxide hydrolase (mEH), a phase II detoxifying enzyme, was 4-fold induced, with a 20-fold increase in the mRNA level during PCM. In contrast to the PCM-induced changes in hepatic morphology, PCM rats supplemented with cysteine showed an increase in the GSH level and well-preserved hepatic structures with mild fat degeneration. Cysteine supplementation inhibited the activation of AP-1 and the induction of mEH in PCM rats. These results provided evidence: (i) that PCM alters liver morphology with a decrease in the glutathione level; (ii) that cysteine may serve as a key element responsible for preserving hepatic morphology and maintaining the glutathione level; and (iii) that cysteine was active in preventing the activation of AP-1 and mEH induction in the liver during PCM.

Animals↗
PubMed2001

Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogs.

The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 200 mg/kg/day (4.71 and 15.3 microg h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration.

Administration, Oral↗
PubMed2001

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.

Administration, Oral↗
PubMed2001

Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant Nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects.

The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to alpha- and beta-globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration-time curve from time zero to time infinity (1012 compared with 2472 microg min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 microg, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0-30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats.

Acetylglucosaminidase↗
PubMed2001

Increased expression of cFLIP(L) in colonic adenocarcinoma.

During tumour progression, cancer cells use diverse mechanisms to escape from apoptosis-inducing stimuli, which may include receptor internalization, inhibition of signal pathways, and regulation of specific sets of genes. Substantial numbers of colon cancer cells have been observed to express Fas/Fas ligand, but are resistant to Fas-mediated apoptosis, suggesting that colonic tumours might develop specific mechanisms to overcome Fas-mediated apoptosis. Recently, cellular FLICE-like inhibitory protein (cFLIP) has been identified as an endogenous inhibitor of Fas- or other receptor-mediated apoptosis and its altered high expression has a suspected association with tumour development or progression. In an effort to investigate the prevalence of cFLIP(L) alterations in colon carcinomas and their possible implications for the progression of colon cancers, cFLIP(L) expression was analysed in adenocarcinomas and adenomatous polyps of colon, with matched normal tissues, at RNA and protein levels, by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. cFLIP(L) transcripts were constitutively expressed in colon cancers and expression levels were significantly higher in carcinomas than in normal tissues (p<0.05). Overexpression of cFLIP(L) protein was found exclusively in carcinoma cells in all matched sets analysed and approximately three-fold induction was detected in cancer cells (p<0.05). The expression of cFLIP(L) protein was not significantly altered in adenomatous polyps compared with normal tissues. Taken together, these results strongly suggest that abnormal overexpression of cFLIP(L) is a frequent event in colon carcinomas and might contribute to in vivo tumour transformation.

Adenocarcinoma↗
PubMed2001

Source of errors in the evaluation of early rectal cancer by endoluminal ultrasonography.

PURPOSE: Although preoperative evaluation of early rectal cancers can be done by endoluminal sonography and by means of colonoscopic findings, it is still controversial whether endoluminal sonography can effectively discriminate mucosal from submucosal lesions. This study was performed to verify objective causes of errors in the evaluation of early rectal cancer (T0/1) using a review of videotaped endoluminal sonography images. METHODS: Eighty-nine patients with suspected early rectal cancer on endoluminal sonography were included. Two different scanners with appropriate probes were used according to tumor location, i.e., transrectal ultrasonography was used to scan up to 8 cm of the rectum above the anal verge, whereas endoscopic ultrasonography was used to assess higher lesions. Endoluminal sonography images were correlated with histologic infiltration and were reevaluated carefully to identify sources of errors. RESULTS: Sensitivity and specificity were 83.1 and 96.5 percent, respectively, for tumor staging, whereas sensitivity was very low compared with specificity (16.7 vs. 90.2 percent) for metastatic lymph nodes. Endoluminal sonography images showed irregularity of the underlying tumor border (P < 0.01) and hypoechoic blurring or cutoff of the inner and outer hypoechoic layers (P < 0.001), all of which closely correlated with histologic infiltration of tumor cells. Overstaging occurred more than twice as often as understaging in tumor reevaluation (14 vs. 5 occurrences). In contrast to tumors, lymph nodes showed a similar amount of both overstaging (four cases) and understaging (five cases). The sources of errors were summarized as five types: false instrumentation, interpretive errors, anatomic defects, imaging failure, and inevitable errors. CONCLUSIONS: Because false instrumentation, interpretive errors, and anatomic defects were considered preventable, 23 (82.1 percent) of the 28 errors might have been avoided. Therefore, a clear image by endoluminal sonography can effectively distinguish mucosal from submucosal lesions in early rectal cancer.

Diagnosis, Differential↗
PubMed2001

The transport of a hepatoprotective agent, isopropryl 2-(1-3-dithiethane-2-ylidene)-2[N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439), across Caco-2 cell monolayers.

Isopropryl 2-(1-3-dithiethane-2-ylidene)-2[N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439) is currently under phase II clinical trials by the Yuhan Research Center for use as a hepatoprotective agent. Unfortunately, the oral bioavailbility of YH439, which is sparingly soluble in water (i.e., 0.3 microg/ml or 0.91 microM at room temperature), reportedly, is negligible regardless of the dose administered to rats in the 10-300 mg/kg range. The bioavailability of the compound increased up to 24%, when administered in the form of a micellar solution (700 microg/ml or 2.1 mM for YH439) at a dose of 10 mg/kg, suggesting that its limited solubility is associated with its negligible bioavailability. In order to obtain additional information concerning the bioavailability of YH439, the mechanism(s) involved in gastrointestinal (GI) absorption were investigated in the present study. For this purpose, the transport of YH430 across a Caco-2 cell monolayer was measured in a Transwell. A permeability of 4.07 x 10(-5) cm/s was obtained for the absorptive (i.e., apical to basolateral direction) transport of 0.42 pM YH439, implicating that the in vivo GI absorption is nearly complete. The absorptive transport exhibited a slight concentration-dependency with an intrinsic clearance (CLi) of 0.38 microLL/cm2/sec, which accounted for 28.1% of the total intrinsic clearance (i.e., CLi plus the intrinsic clearance for the linear component) of the transport. Thus, saturation of the absorption process appears to be a minor factor in limiting the bioavailability of the compound. The apparent permeability of YH439 from the basolateral to the apical direction (i.e., efflux, 6.67 x 10(-5) cm/s) was comparable to that for absorptive transport, but, interestingly, a more distinct concentration-dependency was observed for this transport. However, the efflux does not appear to influence the bioavailability of the compound, as evidenced by the sufficiently high permeability in the absorption direction. Rather, a reportedly extensive first-pass hepatic metabolism appears to be a principal factor in limiting the bioavailability. In this respect, reducing the first-pass metabolism by some means would lead to a higher bioavailability of the compound. Thus, elevation of the absorption rate of YH439 becomes a necessity. From a practical point of view, increasing the concentration of YH439 in the GI fluid appears to be a feasible way to increase the absorption rate, because the compound is primarily absorbed via a linear mechanism. In summary, the solubilization of YH439, as previously demonstrated for a micellar solution of the compound, appears to be a practical way to increase the oral bioavailability of YH439.

Biological Availability↗
PubMed2001

Characteristics of Helicobacter pylori infection in Jamaican adults with gastrointestinal symptoms.

Helicobacter pylori infection is common in Jamaica. Describing its epidemiology in a population-based study depends largely on serology, but serologic assays have not been validated in this population. To address this issue, we examined the presence of H. pylori infection in 30 sequential adult patients with gastroduodenal symptoms by three biopsy-based methods (rapid urease test, histology, and culture) as well as by one research and two commercial enzyme-linked immunosorbent assays (ELISAs). A patient was considered H. pylori positive if the organism was detected by at least one biopsy-based method. Eighteen (60%) of the 30 patients were H. pylori positive by these criteria, whereas 21 (70%) were seropositive for H. pylori immunoglobulin G by our research ELISA. The presence of H. pylori infection in patients with gastric cancer and those with chronic gastritis was missed by biopsy-based methods but was detected by serologic assays. This observation indicates that serologic assays may be better suited for the detection of this infection in a population in which H. pylori-associated pathology is prevalent. The performance of our research ELISA in detecting biopsy-based H. pylori-positive cases was excellent, with a sensitivity and specificity of 100% and 75%, respectively. Molecular genotyping of the isolates revealed that the predominant H. pylori genotypes in this cohort of Jamaicans were cagA(+) vacA slb-m1, and iceA2. The validated serologic assay enables us to interpret epidemiologic data from population-based studies in Jamaica by comparison to those from other populations.

Adult↗
PubMed2001

Costunolide induces apoptosis by ROS-mediated mitochondrial permeability transition and cytochrome C release.

Costunolide is an active compound isolated from the root of Saussurea lappa Clarks, a Chinese medicinal herb, and is considered a therapeutic candidate for various types of cancers. Nevertheless, the pharmacological pathways of costunolide are still unknown. In this study, we investigate the effects of costunolide on the induction of apoptosis in HL-60 human leukemia cells and its putative pathways of action. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials, we show that costunolide is a potent inducer of apoptosis, and facilitates its activity via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in costunolide-treated cells were blocked by the antioxidant N-acetylcystein (NAC). Cyclosporin A, a permeability transition inhibitor, also inhibited mitochondrial permeability transition and apoptosis. Our data indicate that costunolide induces the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of costunolide.

Animals↗
PubMed2001

Bioequivalence of two aceclofenac tablet formulations after a single oral dose to healthy male Korean volunteers.

A bioequivalence study of aceclofenac tablets (test formulation: Dong-A, reference formulation: Airtal) was conducted in 16 healthy male Korean volunteers who received each medicine at a dose of 100 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of aceclofenac were monitored by high-performance liquid chromatography over a period of 24 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and non-transformed tmax. There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 1.04 (0.93 to approximately 1.17) and 0.99 (0.91 to approximately 1.08), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value for tmax was 0.75 (0.00 to approximately 1.00). Moreover, the modified Pitman-Morgan's adjusted F-test indicated that the bioavailabilities of aceclofenac in the 2 medications were comparable regarding intra- and interindividual variability. Therefore, these results indicate that the 2 medications of aceclofenac are bioequivalent and, thus, may be prescribed interchangeably.

Administration, Oral↗
PubMed2001

Bioequivalence of clarithromycin tablet formulations assessed in Korean males.

AIM: Determination of the bioequivalence of 2 clarithromycin tablet formulations manufactured in Korea. PATIENTS AND METHODS: Twenty-four healthy male Korean volunteers received each of the 2 clarithromycin formulations at a dose of 250 mg in a 2 x 2 crossover study. There was a one-week washout period between doses. Plasma concentrations of clarithromycin were monitored by high-performance liquid chromatography over a period of 12 hours after administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated using the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax and untransformed Tmax. RESULTS: The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 0.971 (0.886 approximately 1.063) and 0.982 (0.868 approximately 1.107), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. The corresponding value of Tmax was 0.000 (-0.250 approximately 0.250). CONCLUSION: These results indicate that the 2 medications of clarithromycin are bioequivalent and, thus, may be prescribed interchangeably.

Adult↗
PubMed2001

Helicobacter pylori infection in the Caribbean: update in management.

Helicobacter pylori infection of the stomach is one of the commonest chronic infections worldwide and in the Caribbean, over 50% of the population are affected. H pylori is probably transmitted from person to person by oro-faecal and oro-oral means. H pylori is directly associated with peptic ulcer disease, chronic antral gastritis, gastric carcinoma and B-cell lymphoma of the stomach. In patients with peptic ulcers and H pylori infection, eradication of infection with antibiotics significantly decreases recurrence of ulcers. All patients with H pylori related disease should be tested and treated if positive. The treatment of H pylori infection has evolved over the years but at present triple therapy which includes two antibiotics is recommended.

Anti-Bacterial Agents↗
PubMed2001

Coordination of pancreatic HCO3- secretion by protein-protein interaction between membrane transporters.

Increasing evidence suggests that protein-protein interaction is essential in many biological processes including epithelial transport. In this report, we discuss the significance of protein interactions to HCO(3)(-) secretion in pancreatic duct cells. In pancreatic ducts HCO(3)(-) secretion is mediated by cystic fibrosis transmembrane conductance regulator (CFTR) activated luminal Cl(-)/HCO(3)(-) exchange activity and HCO(3)(-) absorption is achieved by Na(+)-dependent mechanisms including Na(+)/H(+) exchanger 3 (NHE3). We found biochemical and functional association between CFTR and NHE3. In addition, protein binding through PDZ modules is needed for this regulatory interaction. CFTR affected NHE3 activities in two ways. Acutely, CFTR augmented the cAMP-dependent inhibition of NHE3. In a chronic mechanism, CFTR increases the luminal expression of Na(+)/H(+) exchange in pancreatic duct cells. These findings reveal that protein complexes in the plasma membrane of pancreatic duct cells are highly organized for efficient HCO(3)(-) secretion.

Animals↗
PubMed2001

Cl(-)-dependent HCO3- transport by cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis (CF) affects the function of multiple organs. The inability to maintain luminal hydration of ducts leads to their plugging and destruction of the affected organs. An exacerbating problem is the acidic pH of the fluid produced by CF patients' secretory glands. This is best documented for pancreatic secretion. Alkaline fluid secretion requires vectorial transport of electrolytes and of HCO(3)(-). The mechanism of HCO(3)(-) secretion by cystic fibrosis transmembrane conductance regulator (CFTR) expressing cells is not well understood. In the present communication we discuss results suggesting that CFTR itself can transport large amounts of HCO(3)(-) and that HCO(3)(-) transport by CFTR is mediated by a coupled, Cl(-)-dependent process that is different from a simple HCO(3)(-) conductance.

Chloride-Bicarbonate Antiporters↗
PubMed2001

Stability, blood partition and protein binding of an antifibrotic agent, oltipraz.

The stability, blood partition and factors influencing the binding of oltipraz to 4% human serum albumin (HSA) were evaluated. Oltipraz was relatively stable in various pH (1-12) solutions for up to 48-h incubation, however, it was unstable in pH 13 solution and rat plasma and urine. Oltipraz reached an equilibrium fast (within 30 s mixing manually) between plasma and blood cells o f rabbit blood and the plasma-to-blood cells concentration ratios were independent of initial blood concentrations of oltipraz, 1 and 5 microg/ml; the ratios ranged from 0.908 to 1.004. The binding of oltipraz to 4% HSA was independent of oltipraz concentrations ranging from 1 to 100 microg/ml using an equilibrium dialysis technique: the mean value was 95.0%. However, the binding of oltipraz was dependent on HSA concentrations (the low concentrations, 3, 2, 1 and 0.5% of HSA caused an increase in the unbound fraction of oltipraz by 1.32, 1.98, 3.44 and 5.31 times, respectively, compared with the mean value from 4-6% HSA), incubation temperature (the unbound fractions at 37 degrees C and 22 degrees C increased 1.89 and 1.73 times, respectively, than that at 4 degrees C) and the buffer pHs (the unbound fractions were 6.36, 6.51, 5.60 and 4.63% for buffer pHs of 5.8, 6.4, 7.4 and 8.0, respectively).

Animals↗
PubMed2001

No effect of cysteine on the pharmacokinetics of intravenous azosemide in rats with protein-calorie malnutrition by pretreatment with 3-methylcholanthrene.

The effects of cysteine on the pharmacokinetics of azosemide were investigated after intravenous administration of drug, 10 mg/kg, to male Sprague-Dawley rats pretreated with 3-methylcholanthrene fed on 23% protein diet (control rats) and 5% protein diet without (rats with protein-calorie malnutrition, PCM) or with (rats with PCMC) oral cysteine (250 mg/kg, twice daily starting from the fourth week) for 4 weeks. After intravenous administration to rats with PCM, the metabolites of azosemide excreted in urine and recovered from gastrointestinal tract decreased significantly than those in control rats, however, the plasma concentrations, total area under plasma concentration-time curve from time zero to time infinity (AUC) and time-averaged total body clearance (CL) were not significantly different between two groups of rats. It was reported that after intravenous administration of azosemide, 10 mg/kg, to rats with PCMC without pretreatment 3-methylcholanthrene, some pharmacokinetic parameters restored fully or more than the level of control rats; the time-averaged nonrenal clearance and apparent volume of distribution at steady state were comparable to those in control rats, but the terminal half-life and mean residence time were significantly shorter, AUC was significantly smaller, and time-averaged renal clearance and CL were significantly faster than those in control rats. However, the above mentioned effects of cysteine on the pharmacokinetic parameters of azosemide in rats with PCM were not observed with pretreatment with 3-methylcholanthrene.

Animals↗
PubMed2001

Blood partition and protein binding of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378.

The blood partition of KR-31378 between plasma and blood cells and the factors influencing the binding of the drug to 4% human serum albumin (HSA) using an equilibrium dialysis technique were evaluated. KR-31378 reached an equilibrium rapidly between plasma and blood cells of rabbit blood. The equilibrium plasma/blood cells concentration ratios were independent of initial rabbit blood concentrations of KR-31378, 1, 10 and 50 microg/ml; the values were in the range of 1.42-2.33. It took approximately 12-h incubation to reach an equilibrium between plasma and isotonic Søresen phosphate buffer of pH 7.4 containing 3% dextran ('the buffer'). The binding of KR-31378 to 4% HSA was dependent on HSA concentrations (the binding values were 25.3 and 32.0% for HSA concentrations of 2 and 5%, respectively), incubation temperature (the binding values were 48.8, 29.0 and 25.8% for 4, 22 and 37 degrees C, respectively), pHs of isotonic Sørensen phosphate buffer containing 3% dextran (the binding values were 17.7, 20.6, 22.8, 25.6 and 29.5% for buffer pHs of 5.8, 6.4, 7.0, 7.4 and 8.0, respectively) and alpha-1-acid glycoprotein (AAG) concentrations (the binding values were 25.6, 29.9, 34.4 and 50.3% for AAG concentrations of 0, 0.08, 0.16 and 0.32%, respectively).

Animals↗