Search PubMed⌕ Search

Biomedical subjects

M G Lee

Publications and source records attributed to M G Lee.

At least 127 records · Page 7Linked to original sources
PubMed1999

Stability, blood partition, and protein binding of NQ12, a new naphthoquinone derivative.

The stability of a new phospholipase A2 inhibitor, NQ12, in various pH solutions, human plasma, urine, and gastric juices, and rat liver homogenate, the blood partition of NQ12 between plasma and blood cells of rat blood, and the factors influencing the binding of NQ12 to 4% human serum albumin (HSA) using an equilibrium dialysis technique were evaluated. NQ12 was unstable in various pH solutions, human plasma and urine, and rat liver homogenate when incubated in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. However, NQ12 was stable for up to 3-hr incubation in human gastric juice. The plasma-to-blood cell concentration ratios of NQ12 were independent of NQ12 rat blood concentrations when the whole blood was incubated for up to 2-hr; the mean (+/- standard deviation) values were 0.112 +/- 0.0650 and 0.172 +/- 0.105 at initial blood NQ12 concentrations of 10 and 20 microg/ml, respectively. The binding of NQ12 to 4% HSA was considerable (higher than 99%) at NQ12 concentrations ranging from 10 to 100 microg/ml in 4% HSA. The unbound fraction of NQ12 was dependent on NQ12 concentrations, pHs of buffer, and HSA concentrations, but was independent of the concentrations of sulfisoxazole or salicylic acid, incubation temperature, buffers containing various concentrations of chloride ion, and concentrations of heparin and alpha-1-acid glycoprotein.

Animals↗
PubMed1999

Determination of a new asiatic acid derivative, AS 2-006A in rat plasma and urine, and human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed for the determination of a new wound healing agent, AS 2-006A (ethoxymethyl 2-oxo-3, 23-O-isopropylideneasiatate), in rat plasma and urine, and human plasma. The sample preparation was simple: 2 volumes of acetonitrile were added to the biological samples to deproteinize it. A 50-microl aliquot of the supernatant was injected onto the reversed-phase column. The mobile phase employed was acetonitrile : H2O (9:1, v/v) and run at a flow rate of 1.1 ml/min. The column effluent was monitored by a UV detector set at 205 nm. The retention time for AS 2-006A was approximately 29.5 min. The detection limits for AS 2-006A in rat and human plasma were both 1 microg/ml, and in rat urine was 2 microg/ml. The coefficients of variation of the assay (within-day and between-day) were generally low (below 10.8%) for rat plasma and urine, and human plasma. No interferences from endogenous substances were found.

Animals↗
PubMed1999

Effects of dexamethasone on the pharmacokinetics of adriamycin after intravenous administration to rats.

Adriamycin was metabolized to adriamycinol by the cytoplasmic aldo-keto reductase and adriamycin and adriamycinol were further metabolized to their deglycosylated aglycones, M3 and M4, respectively, by cytochrome P450. SKF-525A (a cytochrome P450 inhibitor) and dexamethasone (a cytochrome P450 inducer) were pretreated to rats. Adriamycin, 16 mg/kg, was infused over 1-min via the jugular vein of each rat. After pretreatment with SKF-525A, the area under the plasma concentration-time curve of adriamycin from time zero to the last measured time in plasma, 8 h (537 versus 155 microg x min/ml) was significantly greater, and the 24-h urinary excretion of M3 (1.65 versus 23.8 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (33.7 versus 3.38 microg) were significantly smaller than those in control rats suggesting that the formation of M3 and M4 were inhibited by SKF-525A. After pretreatment with dexamethasone, the 24-h urinary excretion of M3 (94.5 versus 23.8 microg), M4 (8.43 versus 2.78 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (116 versus 33.7 microg) were significantly greater than those in control rats, suggesting that the formation of M3 and M4 seemed to be induced by dexamethasone.

Animals↗
PubMed1999

Pharmacokinetics of a chemoprotective agent, 2-(allylthio)pyrazine, after intravenous and oral administration to rats: hepatic and gastric first-pass effects.

Pharmacokinetic parameters of 2-(allylthio)pyrazine (2-AP) were evaluated after i.v. administration of the drug (10, 20, 50, and 100 mg/kg body weight) and oral administration of the drug (10, 50, and 100 mg/kg body weight) to rats. The hepatic, gastric, and intestinal first-pass effects of 2-AP were also measured after i.v., intraportal, intraduodenal, and oral administration of the drug (10 and 50 mg/kg body weight) to rats. After i.v. administration, the pharmacokinetic parameters of 2-AP were dose-independent at the dose ranges studied. However, after oral administration, the dosenormalized total area under the plasma concentration-time curve from time zero to time infinity values (43.5, 125, and 205 microg min/ml, based on 10 mg/kg body weight) increased significantly with increasing doses. The extent of absolute oral bioavailability (F) values also increased with increasing oral doses; the values were 19. 6, 56.7, and 93.6% for 10, 50, and 100 mg/kg body weight, respectively. The oral data above could be due to saturable hepatic, gastric, and/or intestinal first-pass effects. This was proved by saturable gastric first-pass effect (the significant area under the plasma concentration-time curve from time zero to time infinity difference between oral and intraduodenal administration of 2-AP); the values were 62.6 and 26.6% at 2-AP doses of 10 and 50 mg/kg body weight, respectively. Approximately 20% of oral dose was eliminated by liver (hepatic first-pass effect) for both oral doses of 10 and 50 mg/kg body weight. However, the first-pass effects of 2-AP in the intestine, heart, and lung were almost negligible. The low F value after oral administration of 2-AP at low dose (10 mg/kg body weight) was mainly due to gastric first-pass effect in rats.

Administration, Oral↗
PubMed1998

Membrane-limited expression and regulation of Na+-H+ exchanger isoforms by P2 receptors in the rat submandibular gland duct.

1. Cell-specific reverse transcriptase-polymerase chain reaction (RT-PCR), immunolocalization and microspectrofluorometry were used to identify and localize the Na+-H+ exchanger (NHE) isoforms expressed in the submandibular gland (SMG) acinar and duct cells and their regulation by basolateral and luminal P2 receptors in the duct. 2. The molecular and immunofluorescence analysis showed that SMG acinar and duct cells expressed NHE1 in the basolateral membrane (BLM). Duct cells also expressed NHE2 and NHE3 in the luminal membrane (LM). 3. Expression of NHE3 was unequivocally established by the absence of staining in SMG from NHE3 knockout mice. NHE3 was expressed in the LM and in subluminal regions of the duct. 4. Measurement of the inhibition of NHE activity by the amiloride analogue HOE 694 (HOE) suggested expression of NHE1-like activity in the BLM and NHE2-like activity in the LM of the SMG duct. Several acute and chronic treatments tested failed to activate NHE activity with low affinity for HOE as expected for NHE3. Hence, the physiological function and role of NHE3 in the SMG duct is not clear at present. 5. Activation of P2 receptors resulted in activation of an NHE-independent, luminal H+ transport pathway that markedly and rapidly acidified the cells. This pathway could be blocked by luminal but not basolateral Ba2+. 6. Stimulation of P2U receptors expressed in the BLM activated largely NHE1-like activity, and stimulation of P2Z receptors expressed in the LM activated largely NHE2-like activity. 7. The interrelation between basolateral and luminal NHE activities and their respective regulation by P2U and P2Z receptors can be used to co-ordinate membrane transport events in the LM and BLM during active Na+ reabsorption by the SMG duct.

Adenosine Triphosphate↗
PubMed1998

The 3' untranslated region of the hsp 70 genes maintains the level of steady state mRNA in Trypanosoma brucei upon heat shock.

An increase in the transcriptional efficiency at elevated temperatures is a characteristic of transcription of heat shock protein (hsp) coding genes in most eukaryotes analyzed to date. The regulatory mechanism for hsp 70 genes expression in Trypanosoma brucei does not follow the conventional transcriptional induction mechanism. The hsp 70 locus of T.brucei appears in a permanently activated state, and transcriptional induction of hsp 70 genes by heat shock does not occur in this organism. Therefore, the differential expression of the hsp 70 genes in trypanosomes is, to a large extent, post-transcriptionally controlled. Mechanisms of post-transcriptional control of the hsp 70 gene expression were investigated. Procyclic trypanosomes were normally maintained at approximately 25 degreesC. Incubation of procyclic trypanosomes at 41 degreesC drastically reduced the steady state mRNA levels of many protein coding genes. In contrast, the expression of the hsp 70 genes is either maintained at a high level or is up-regulated. The hsp 70 intergenic region promoter together with its 3' splice acceptor sites and the 5' untranslated region (UTR) are not sufficient to maintain or up-regulate the mRNA level of a reporter gene upon heat shock. However, addition of the 3' UTR of hsp 70 genes to a reporter gene, driven by different promoters, maintained a high level expression of the mRNA during heat shock. These results suggested that the 3' UTR of the hsp 70 genes is primarily responsible for the maintenance of mRNA level during heat shock, while mRNA containing the 3' UTR from many other genes may be rapidly degraded by heat shock induced processes.

Animals↗
PubMed1998

Nociception activates Elk-1 and Sap1a following expression of the ORL1 receptor in Chinese hamster ovary cells.

Nociceptin stimulation of the ORL1 receptor expressed in Chinese hamster ovary (CHO) cells results in the activation of the extracellular signal regulated kinases ERK1 and ERK2. ERK1/ERK2 activation is inhibited by pertussis toxin, the MEK inhibitor PD 98059 and by transient expression of alpha-transducin, indicating that ORL1 up-regulation of these kinases occurs as a consequence of the release of the G-protein betagamma complex following the activation of pertussis-toxin sensitive Galphai-family G-proteins. Using specific reporter genes we demonstrate that the transcription factors Elk-1 and Sapla are activated in a pertussis toxin-sensitive manner as a consequence of ORL1 upregulation of ERK1/ERK2 to induce changes in gene expression. The activation of these transcription factors is also inhibited following treatment with PD 98059 and following coexpression of alpha-transducin.

Animals↗
PubMed1998

Determination of a chemoprotective agent, 2-(allylthio)pyrazine, in plasma, urine and tissue homogenates by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed for the determination of a chemoprotective agent, 2-(allylthio)pyrazine (I), in human plasma and urine, and in rat blood and tissue homogenate using diazepam as an internal standard. The sample preparation was simple; 2.5 volumes of acetonitrile were added to the biological sample to deproteinize it. A 50-100 microl aliquot of the supernatant was injected onto a C18 reversed-phase column. The mobile phase employed was acetonitrile-water (55:45, v/v), and it was run at a flow-rate of 1.5 ml/min. The column effluent was monitored using an ultraviolet detector at 330 nm. The retention times for I and the internal standard were 4.0 and 5.1 min, respectively. The detection limits of I in human plasma and urine, and in rat tissue homogenate (including blood) were 20, 20 and 50 ng/ml, respectively. The coefficients of variation of the assay (within-day and between-day) were generally low (below 6.1%) in a concentration range from 0.02 to 10 microg/ml for human plasma and urine, and for rat tissue homogenate. No interferences from endogenous substances were found.

Animals↗
PubMed1998

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.

Calcitonin-gene-related peptide (CGRP) and adrenomedullin are related peptides with distinct pharmacological profiles. Here we show that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-transmembrane-domain proteins, which we have called receptor-activity-modifying proteins or RAMPs, are expressed. RAMPs are required to transport CRLR to the plasma membrane. RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor. RAMP2-transported receptors are core-glycosylated and are adrenomedullin receptors.

3T3 Cells↗
PubMed1998

Pharmacokinetics of a non-narcotic analgesic, DA-5018, in rats.

The pharmacokinetics of a non-narcotic analgesic, DA-5018, were compared after single intravenous (i.v.), subcutaneous (s.c.), and oral administrations, and after multiple (seven consecutive days) s.c. administration to rats. After i.v. administration of DA-5018, 1, 2, and 5 mg kg-1, the pharmacokinetic parameters of DA-5018 were independent of the dose ranges studied. After oral administration of DA-5018, absorption of the drug from gastrointestinal (GI) tract was fast, but the extent of absolute bioavailability (F) was low; the values were 23.2, 23.0, and 27.3% for 2, 5, and 10 mg kg-1, respectively. After single s.c. administration of DA-5018, absorption of the drug from the injected site was fast and the extent of absorption was fairly good; the F values were 74.5 and 71.8% for 2 and 5 mg kg-1, respectively. The lower F values after oral administration of DA-5018 to rats could be due to degradation of the drug in rat GI tract and/or considerable first-pass effect. After i.v., oral, and s.c. administration of DA-5018, the drug had a strong affinity to the rat tissues studied as reflected in the greater-than-unity tissue to plasma ratio. After i.v., oral, and s.c. administration of the drug, the biliary and urinary excretion of unchanged DA-5018 were negligible. There was no significant difference in the pharmacokinetics or tissue distribution of DA-5018 between single and multiple s.c. administration of the drug, 5 mg kg-1, to rats, indicating that there could be no tissue accumulation of the drug after multiple s.c. administration of the drug to rats.

Administration, Oral↗
PubMed1998

Pharmacokinetic changes of M1, M2, M3 and M4 after intravenous administration of a new anthracycline, DA-125, to rats pretreated with phenobarbital, 3-methylcholanthrene, chloramphenicol, or SKF-525A.

The pharmacokinetics of M1-M4, the metabolites of a new anthracycline antineoplastic agent, DA-125, were compared after intravenous (i.v.) administration of DA-125, 15 mg kg-1, to rats pretreated with enzyme inducers, such as phenobarbital (PBT, n = 14) and 3-methylcholanthrene (MCT, n = 15), or enzyme inhibitors, such as SKF-525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After i.v. administration of DA-125, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous formation of M2 from M1. The AUC0-8 h of M1 (47.1 versus 7.85 micrograms min mL-1) and M2 (20.7 versus 44.3 micrograms min mL-1) decreased significantly in the PBT group compared to those in the PBC group. However, the corresponding value of only M1 (74.6 versus 89.9 micrograms min mL-1) decreased significantly in the MCT group. The above data indicate that metabolism of M1 is increased by pretreatment with both PB and 3-MC, and that of M2 with PB, but not with 3-MC. The AUC0-8 h of both M1 (126 versus 78.5 micrograms min mL-1) and M2 (69.2 versus 44.3 micrograms min mL-1) increased significantly in the SKT group compared to the SKC group. However, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of both M1 and M2 is inhibited by pretreatment with SKF-525A, but not with CM.

Animals↗
PubMed1998

Pharmacokinetic and pharmacodynamic changes of azosemide after intravenous and oral administration of azosemide to uranyl nitrate-induced acute renal failure rats.

The pharmacokinetic and pharmacodynamic differences of azosemide were investigated after intravenous (i.v.) and oral administration of azosemide, 10 mg kg-1, to the control and uranyl nitrate-induced acute renal failure (U-ARF) rats. After IV administration, the plasma concentrations of azosemide were significantly higher in the U-ARF rats and this resulted in a significant increase in AUC (2520 versus 3680 micrograms min mL-1) and significant decrease in Cl (3.96 versus 2.72 mL min-1 kg-1) of azosemide. The significant decrease in Cl in the U-ARF rats was due to the significant decrease in Clr of azosemide (1.55 versus 0.00913 mL min-1 kg-1) due to the decrease in kidney function in the U-ARF rats. After IV administration, the urine output (38.5 versus 8.45 mL 100 g-1 body weight) and urinary excretion of sodium (4.60 versus 0.420 mmol 100 g-1 body weight) decreased significantly in the U-ARF rats. After oral administration, the AUC0-8 h of azosemide decreased significantly (215 versus 135 micrograms min mL-1) in the U-ARF rats possibly due to the decreased GI absorption of azosemide. After oral administration, the 24-h urine output decreased considerably (16.1 versus 11.2 mL 100 g-1 body weight, p < 0.098) and the 24-h urinary excretion of sodium (1.74 versus 0.777 mmol 100 g-1 body weight) decreased significantly in the U-ARF rats. The i.v. and oral doses of azosemide needed to be modified in the acute renal failure patients if the present rat data could be extrapolated to humans.

Acute Kidney Injury↗
PubMed1998

Pharmacokinetics and tissue distribution of a new carbapenem DA-1131, after intravenous administration to mice, rats, rabbits and dogs.

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA-1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After i.v. administration to mice (20, 50, 100, and 200 mg kg-1), rats (50, 100, 200, and 500 mg kg-1), rabbits (20, 50, 100, and 200 mg kg-1), and dogs (10, 20, 50, 100, and 200 mg kg-1), the pharmacokinetic parameters of DA-1131 seemed to be independent of DA-1131 doses studied in all four animal species. However, the renal clearance of percentage of i.v. dose of DA-1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg-1) and dogs (from 100 mg kg-1) due to reduced kidney function induced by DA-1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg-1 compared with that in the control rabbits (0.466 versus 4.31 mL min-1 kg-1). Renal active secretion of DA-1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA-1131 was observed in dogs. Although DA-1131 was widely distributed in all tissues studied in mice (20-200 mg kg-1), rats (200 mg kg-1), rabbits (50 mg kg-1), and dogs (50 mg kg-1) affinity of DA-1131 for tissues was low: the tissue-to-plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA-1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147-187 mL kg-1), rabbits (91.7-148 mL kg-1), and dogs 243-298 mL kg-1). The contribution of biliary excretion of unchanged DA-1131 to nonrenal clearance of DA-1131 seemed to be minor in rats (200 mg kg-1) and dogs (50 mg kg-1); the percentages of i.v. dose excreted in 8 h bile as unchanged DA-1131 were 1.76 and 2.71% after i.v. administration of the drug to rats and dogs, respectively.

Animals↗
PubMed1998

Interspecies pharmacokinetic scaling of a new carbapenem, DA-1131, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics.

The total body clearance (CI), renal clearance (CIr), and apparent volume of distribution at steady state (Vss) of DA-1131, a new carbapenem, after intravenous (iv) administration of the drug, 50 mg kg-1, to mice, rats, rabbits, and dogs were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict these parameters in humans. Significant linear relationships were obtained between log[CI (L h-1)] and log[W (kg)] (r = 0.995; p = 0.00503), log [CI, (L h-1)] and log [W (kg)] (r = 0.998; p = 0.0429), and log [Vss (L)] and log [W (kg)] (r = 0.987; p = 0.0126). The corresponding allometric equations were CI = 0.706W 0811, CIr = 0.318W 0.888, an V88 = 0.194W 0981. These allometric equations were extrapolated to predict the CI and Vss for DA-1131 in humans based on 70 kg body weight. The CI and Vss for humans predicted from the four animal data well fitted to regression lines of animal data. Interspecies scale-up of plasma concentration-time data for the four species using a complex Dedrick plot resulted in similar profiles. In addition, the concentration in plasma-time profile predicted that the DA-1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

Animals↗
PubMed1998

Pharmacokinetics of a new carbapenem, DA-1131, after intravenous administration to rats with alloxan-induced diabetes mellitus.

Because physiological changes occurring in diabetes patients could alter the pharmacokinetics of drugs used to treat the disease, the pharmacokinetics and tissue distribution of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous (i.v.) administration of the drug, 50 mg kg-1, to control and alloxan-induced diabetes mellitus (AIDM) rats. The impaired kidney function was observed by pretreatment with alloxan based on physiological parameters of plasma, creatinine clearance, and the kidney microscopy. After 1-min i.v. infusion of DA-1131, the plasma concentrations of DA-1131 and the total area under the plasma concentration-time curve of DA-1131 from time zero to time infinity (AUC) increased significantly in the AIDM rats (7350 versus 4400 micrograms min mL-1) when compared with those in control rats. This was due to significantly slower total body clearance (Cl) of DA-1131 (6.80 versus 11.4 mL min-1 kg-1) in AIDM rats than that in control rats. The significantly slower Cl of DA-1131 in AIDM rats was due to significantly slower renal (2.62 versus 4.95 mL min-1 kg-1, because of the considerably decreased glomerular filtration rate of DA-1131) and nonrenal (3.99 versus 6.34 mL min-1 kg-1, possibly because of the considerably slower metabolism in rat liver and kidney) clearance in AIDM rats. The amount of DA-1131 recovered from each rat tissue studied was significantly higher in AIDM rats than that in control rats, however, the tissue to plasma ratios were not significantly different between the two groups of rats.

Alloxan↗
PubMed1998

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus.

Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs to treat the disease, the pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.) and oral administration of the drug (6 mg per whole body weight) to control rats and alloxan-induced diabetes mellitus rats (AIDRs). After i.v. administration, the total body clearance (5.47 versus 7.05 mL min(-1) kg(-1)) was significantly slower in AIDRs and this was due to significantly slower renal clearance (2.35 versus 4.33 mL min(-1) kg(-1)) because the nonrenal clearance was comparable between two groups of rats. The 8 h urinary excretion of furosemide after i.v. administration decreased significantly (2280 versus 3760 microg) in AIDRs due to impaired kidney function; the glomerular filtration rate measured by creatinine clearance was significantly slower (2.86 versus 4.33 mL min(-1) kg(-1)) and both the plasma urea nitrogen (43.5 versus 17.3 mg dL(-1)) and kidney weight (0.953 versus 0.749% of body weight) increased significantly in AIDRs. This resulted in a significant decrease in the 8 h urine output per g kidney (17.8 versus 43.6 mL) in AIDRs. However, the 8 h diuretic efficiency was not significantly different between two groups of rats. After oral administration, the area under the plasma concentration-time curve from time 0 to 8 h decreased significantly in AIDRs (1200 versus 1910 microg x min mL(-1)) due to considerably decreased absorption of furosemide from gastrointestinal tract of AIDRs. After oral administration, the 8 h urine output per g kidney (18.6 versus 36.4 mL) also decreased significantly in the AIDRs due to significantly decreased 8 h urinary excretion of furosemide (405 versus 2210 microg), however, the 8 h diuretic efficiency increased significantly (127 versus 35.2 mL mg(-1)) in AIDRs.

Administration, Oral↗