Biomedical subjects

S J Chung

Publications and source records attributed to S J Chung.

At least 37 records · Page 2Linked to original sources

PubMed2001

Incidence of gastroesophageal malignancy in patients with dyspepsia in Hong Kong: implications for screening strategies.

BACKGROUND: A "test-and-treat" strategy for H pylori infection has been recommended in Europe and North America as safe and cost-effective for management of patients with dyspepsia. The primary aim of this study was to determine the frequency of gastroesophageal cancer in 2 groups of patients with dyspepsia: those 45 years of age or younger without "alarm" symptoms (low-risk group) and patients over 45 years of age or any patient with "alarm" symptoms (high-risk group). A secondary aim was to determine the frequency of gastric cancer among patients in the low-risk group with or without a positive serology for H pylori. METHODS: Patients with persistent dyspepsia were recruited from 4 regional hospitals in Hong Kong. Those in the low-risk group were evaluated for H pylori by using a whole blood serology test; they underwent endoscopy within 1 week. Those in the high-risk group and those taking nonsteroidal anti-inflammatory drugs (NSAIDs) underwent endoscopy promptly. Alarm symptoms were as follows: weight loss (10 or more pounds over 8 weeks), recurrent vomiting, dysphagia, bleeding, or anemia. RESULTS: Of 2627 patients enrolled, 1017 were in the low-risk group and 1610 in the high-risk group. Twenty-three patients (0.9%) had gastroesophageal cancers (20 gastric, 3 esophageal). Four patients with cancer (17.4%) were in the low-risk group (3 gastric, 1 esophageal); all except the patient with esophageal cancer had a positive serology test. In the high-risk group, 19 patients had cancer (17 gastric, 2 esophageal). CONCLUSION: Gastric cancer is relatively frequent among young patients with dyspepsia who have no alarm features in Hong Kong. This finding raises concerns as to the safety of the "test-and-treat" strategy for the management of patients with dyspepsia in Asia.

Adult↗

PubMed2001

Medullary nephrocalcinosis associated with long-term furosemide abuse in adults.

BACKGROUND: The use of furosemide is well recognized as a predisposing factor of nephrocalcinosis in infants. Although furosemide is widely used for various medical conditions in adults, its association with nephrocalcinosis in adults is not well established. METHODS: We studied 18 consecutive adult patients (male:female ratio 1:17, age range 21-59 years) who habitually took furosemide to control weight or oedema for long periods of time (range 3-25 years). The daily dose of continuous intake of furosemide ranged from 40 to 2800 mg. Nephrocalcinosis was evaluated using renal ultrasonography (US), computed tomography (CT), or kidney biopsies. RESULTS: Renal US and CT revealed bilateral nephrocalcinosis of the medullary pyramids in 15 (83.3%) out of 18 patients. The duration of furosemide abuse was similar between nephrocalcinosis positive (NC(+)) and nephrocalcinosis negative (NC(-)) groups. The daily dose of furosemide was nearly 10 times higher in the NC(+) group (range 120-2800 mg, mean 538 mg) than the NC(-) group (range 40-80 mg, mean 67 mg). All patients showed variable degrees of renal insufficiency and there was no difference in creatinine clearance between the NC(+) and NC(-) groups (P>0.05). Kidney biopsies performed in three patients showed focal tubulo-interstitial fibrosis and atrophy and calcifications were observed in outer medullary tubulo-interstitium. CONCLUSIONS: Long-term furosemide abuse can cause medullary nephrocalcinosis in adults, and the risk of developing of nephrocalcinosis seems to be correlated with the daily dose of furosemide. We suggest that long-term furosemide abuse should be suspected in adult patients when medullary nephrocalcinosis is incidentally detected by US or CT.

Adult↗

PubMed2001

Contribution of ion pair complexation with bile salts to biliary excretion of organic cations in rats.

The objective of this study was to examine whether ion pair complexation with endogenous bile salts in hepatocytes contributes to the preferential biliary excretion of organic cations (OCs). Tributylmethylammonium (TBuMA; mol wt 200) and triethylmethylammonium (TEMA; mol wt 116) were selected as model OCs that exhibit significant and negligible biliary excretion, respectively, in rats. The apparent lipophilicity of TBuMA, but not that of TEMA, was increased by the presence of either rat bile or specific bile salts, suggesting the formation of lipophilic ion pair complexes for TBuMA with bile salts in the liver. The uptake of TBuMA into canalicular liver plasma membrane (cLPM) vesicles, but not that of TEMA, was increased in the presence of bile salts, with a significant increase for both ATP-dependent transport and passive diffusion. The uptake of TBuMA in the presence of the bile salts was inhibited by representative P-glycoprotein (P-gp) substrates and vice versa, suggesting the involvement of P-gp in the canalicular excretion of TBuMA-bile salt complexes in vivo. Increased affinity toward P-gp is suggested as the mechanism responsible for the increased ATP-dependent transport for the ion pair complexes. We propose that ion pair formation with bile slats in hepatocytes may be responsible for the preferential biliary excretion of high-molecular-weight OCs including TBuMA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Comparative study of the behavioral and neuropsychologic characteristics of tic disorder with or without attention-deficit hyperactivity disorder (ADHD).

To study the nature of the comorbidity of tic disorder and attention-deficit hyperactivity disorder (ADHD), patients with tic disorder with or without ADHD were compared on the basis of clinical ratings and neuropsychologic tests. Seventy-eight children were involved in this study: 16 with tic disorder, 19 with comorbid tic disorder and ADHD, 21 with ADHD, and 22 normal controls. Rating scales for ADHD, the Child Behavior Checklist and the Yale Global Tic Severity Scale, were completed in clinical groups. To identify differences in neuropsychologic function among the four groups, the results of seven neuropsychologic tests of global cognitive abilities, attention, information-processing capacity, and fine motor skill were compared. On most behavioral and neuropsychologic tests, the tic disorder with ADHD and the ADHD groups demonstrated similar performance patterns and marked deficits compared with the tic disorder and the control groups, whereas in most of the attention tests, the ADHD group made more commission errors than the tic disorder with ADHD group. These findings suggest that the tic disorder with ADHD group has marked cognitive deficits and behavioral disturbance similar to the ADHD group, whereas the tic disorder group is more similar to the controls. The tic disorder with ADHD group might represent a true comorbidity of the two disorders.

Adolescent↗

PubMed2001

The transport of a reversible proton pump antagonist, 5, 6-dimethyl-2-(4-Fluorophenylamino)-4-(1-methyl-1,2,3, 4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride (YH1885), across caco-2 cell monolayers.

5,6-Dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3, 4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride (YH1885) is under development as a novel acid pump antagonist by Yuhan Research Center. Previous studies have suggested that the AUC and C(max) of orally dosed YH1885 are dose-dependent in the range of 2 to 500 mg/kg. The objective of the present study was to investigate the absorption mechanism of YH1885 using a human colon carcinoma cell line, Caco-2. The cells were grown to confluency on a permeable polycarbonate membrane insert to permit loading of YH1885 on either the apical or basolateral side of the cell monolayer. The flux across the monolayer from the apical to basolateral side was 3 to 5 times greater than that from the basolateral to apical side. The uptake of YH1885 into the Caco-2 cell monolayer was saturable and appeared to be mediated by a high-affinity transporter, with an apparent K(m) of 1.47+/-0.21 microM and a V(max) of 25.14+/-1.16 pmol/cm(2)/40 s. The apical to basolateral transport across the monolayer was Na(+)-independent, H(+)-sensitive, and energy-dependent. The transport was inhibited significantly by the presence of structural analogs of YH1885 (e.g., YH957, YH1070, and YH1041), some pyrimidine nucleobases (uracil and 5-methyluracil), and nucleobase transport inhibitors (e.g., papaverine, dipyridamole, and phloridzin). These results demonstrate that the apical to basolateral transport of YH1885 across the Caco-2 cell monolayer is partially mediated by a nucleobase transport system, which exhibits high-affinity and energy-dependent properties for YH1885. Saturation of this transport system, in addition to the limited solubility of YH1885 (i.e., approximately 5.3 microM), appears to contribute to the dose-dependent bioavailability of the drug.

Biological Transport↗

PubMed2000

Syndrome of cerebral spinal fluid hypovolemia: clinical and imaging features and outcome.

OBJECTIVE: To investigate clinical, MRI, and radioisotope findings and therapeutic outcome of the syndrome of CSF hypovolemia. METHODS: Retrospective review was performed of 30 consecutive patients (10 men, 20 women; mean age 37 years) with the syndrome of CSF hypovolemia. RESULTS: All patients had an orthostatic headache, which was alleviated to a variable extent on recumbency. Additional clinical symptoms included nausea, dizziness, neck stiffness, blurring of vision, tinnitus, plugged ear, hearing difficulties and radicular pain of the arm. Eighty-two percent of the patients had CSF opening pressure less than 60 mm H2O, 59% had CSF pleocytosis, and 95% had increased CSF protein. Brain MRI showed diffuse pachymeningeal gadolinium enhancement on T1-weighted image in 83%, which was seen as hyperintense signals on T2-weighted imaging. Other features included subdural hematoma/hygroma in 17% and descent of the brain in 48% of the patients. Radioisotope cisternographic results identified CSF leakage sites in 52%, most often at the lumbar region. Also observed were limited ascent of the tracer to the cerebral convexity (91%), early appearance of radioisotope in the bladder (65%), and early soft tissue uptake of radioisotope (43%). Epidural blood patches were performed in 23 patients, which produced complete resolution of headaches in 70%. Two patients underwent drainage of subdural hematoma. None died or were disabled during hospitalization. CONCLUSIONS: Patients with CSF hypovolemia frequently have distinct MRI and radioisotope cisternographic abnormalities and often respond favorably to an epidural blood patch.

Adult↗

PubMed2000

A novel strategy for designing irreversible inhibitors of metalloproteases: acetals as latent electrophiles that interact with catalytic nucleophile at the active site.

A new strategy for design of irreversible inactivators for carboxypeptidase A (CPA), a prototypic zinc protease, has been developed by exploiting the property of acetals to generate an oxacarbenium ion intermediate in the conversion into the corresponding carbonyl compounds. The design strategy is exemplified by 2-benzyl-5-alkyl-3,5-dioxapentanoic acids (1a-c). Interestingly, (R)-1b is slightly more potent than an (S)-1b as an inactivator of CPA.

Alkanes↗

PubMed2000

Prolonged delivery of nicotine in rats via nasal administration of proliposomes.

In order to achieve a prolonged delivery of nicotine to the systemic circulation, proliposomes containing nicotine base (NB-proliposomes) or nicotine hydrogen tartarate salt (NS-proliposomes) and a mixture of powdered nicotine hydrogen tartarate salt and sorbitol (1:9 mixture, MP) were administered intranasally to rats at a nicotine dose of 1 mg/kg. Proliposomes, lipid-sorbitol mixtures that form liposomes upon contact with water, were prepared according to previously established methods, and the mixture (MP) was prepared by mixing NS powder with sorbitol particles (105-350 micrometer in size). Nasal absorption of nicotine from these formulations was very rapid (i.e. less than 10 min was required to reach plasma peaks) and showed substantially sustained plasma nicotine levels compared to saline solutions of NB and NS, and previously reported nasal nicotine sprays. The AUC values from the proliposomes and MP were comparable to those from the saline solutions of NB and NS. However, the mean residence time (MRT) and plasma half-life (T(1/2beta)) of nicotine in the present study were much larger than those from the saline solutions. Thus, a prolonged delivery of nicotine to systemic circulation via the application of proliposomes or MP intranasally appears feasible. NB-proliposomes exhibited the best characteristics in terms of the area under the plasma concentration (AUC), MRT and T(1/2beta) of nicotine, which was followed by NS-proliposomes and MP. Retarded conversion of proliposomes and MP to liposomal emulsions and solution in the nasal cavity seems responsible, in part, for the sustained plasma nicotine concentrations, since the emulsions and solution yielded very short MRT and T(1/2beta) of nicotine. In addition, reduced metabolism to cotinine from the proliposomes and MP was apparently responsible for the sustained plasma nicotine levels. These dosage forms of nicotine appear to circumvent some of the shortcomings of transdermal patches (i.e. long T(max)) and nasal sprays (i.e. short T(1/2beta) and physicochemical instability).

Administration, Intranasal↗

PubMed2000

The potential replacement of HPLC by 125I-RIA for the characterization of cyclosporin A: a bioavailability study after oral administration in healthy human subjects.

A significant overestimation of cyclosporin A (CsA) by a radioimmunoassay using 125I-labeled monoclonal antibody (125I-RIA), compared to the reference HPLC method, has been reported for a limited number of samples from transplant patients. However, the extent of the discrepancy, with respect to bioavailability parameters, has not been examined for the case of the oral administration of a single dose CsA to healthy subjects where a number of factors which might be involved in this overestimation (e.g. under steady state condition and a significant accumulation of CsA metabolites) would be absent. Therefore, the objective of this study was to assess the effect of potential difference manifested by the two analytical procedures, 125I-RIA and HPLC, on the bioavailability analysis of CsA. An oral CsA formulation was administered to 22 healthy male subjects and the blood samples were analysed by both 125I-RIA and HPLC. Significant discrepancies in the estimated CsA concentrations by the two methods (paired t-test, P < 0.001) were found. The difference (bias) increased with increasing concentrations of blood CsA (P < 0.001). However, despite the bias in CsA estimations, the AUC and Cmax, obtained by 125I-RIA and HPLC methods showed only small differences (i.e. 2% for AUC and 7% for Cmax). Thus, our results suggest that the bias of the 125I-RIA vis-a-vis the HPLC method in the estimation of CsA blood levels may not, in practice, affect the bioavailability analysis (e.g. bioequivalence study) of CsA in a situation where a single dose CsA is orally administered to healthy subjects.

Administration, Oral↗

PubMed2000

Functional impairment of sinusoidal membrane transport of organic cations in rats with CCl4-induced hepatic failure.

PURPOSE: The effect of CCl4-induced experimental hepatic failure (EHF) on the sequential hepatobiliary transport of model organic cations (OCs), triethylmethylammonium (TEMA), and tributylmethylammonium (TBuMA), was investigated in rats. METHODS: EHF was induced by an i.p. injection of CCl4 at a dose of 1 ml/kg 24 hr prior to the transport study. The cumulative in vivo biliary excretion, in vitro hepatic uptake by isolated hepatocytes, in vitro efflux (i.e., release) from hepatocytes, and in vivo hepatobiliary excretion clearance were measured for normal and CCl4-EHF rats. RESULTS: The CCl4-EHF decreased the apparent in vivo biliary clearance (CL(b)) and the in vitro maximum uptake rate (Vmax, uptake) of TBuMA by 66 and 48%, respectively. The CCl4-EHF had no effect on the CL(b) of TEMA. but decreased both the Vmax, uptake (59%) and the in vitro maximum hepatic efflux rate (Vmax, efflux) of TEMA (80%). On the contrary, the CCl4-EHF had no influence on the in vivo hepatobiliary excretion clearance (CL(exc)) of both OCs. CONCLUSIONS: Transport systems for the OCs on the sinusoidal membrane (uptake and/or efflux), rather than those on the bile canalicular membrane (excretion) appear to be prone to damage by the CC14-EHF.

Animals↗

PubMed2000

Giant-sized condyloma of the breast with focal acantholytic changes.

BACKGROUND: A healthy 26-year-old pregnant woman presented with a 6.0-cm exophytic mass in her left inframammary fold. The lesion was surgically excised. METHODS: Histopathologic sections of the skin lesion were reviewed in hematoxylin and eosin-stained slides. Additional sections were studied by an in situ hybridization method for human papillomavirus DNA (HPV) types 6 and 11. RESULTS: The histopathologic examination demonstrated a benign exophytic, verrucous and papillary epidermal proliferation with features of condyloma acuminatum. Reactivity to HPV DNA types 6 and 11 was demonstrated by in situ hybridization method. The epidermis adjacent to, and focally within, the neoplasm showed multiple areas of suprabasilar and intraepidermal acantholysis without dyskeratosis. CONCLUSIONS: Condylomas related to HPV 6 and 11 may be found in extragenital locations including conjunctiva, oral and nasal mucosa. To our knowledge, however, the extragenital condylomas described in the literature have not included the giant-sized variant. We describe an example of a benign, giant-sized condyloma acuminatum of the breast with nearby acantholytic alterations similar to Hailey-Hailey disease.

Adult↗

PubMed2000

Electrocardiographic abnormalities in patients treated with clozapine.

BACKGROUND: Cardiovascular side effects of clozapine are not uncommon, but few systematic studies of these effects have been performed. In this study, we reviewed data on the electrocardiographic (ECG) abnormalities in patients treated with clozapine. METHOD: Sixty-one patients treated with clozapine were selected from the Seoul National University Hospital Treatment-Resistant Schizophrenia Clinic. A retrospective chart review was conducted to identify ECG abnormalities and cardiovascular side effects. RESULTS: The prevalence of ECG abnormalities in patients who had been using antipsychotics other than clozapine was 13.6% at baseline, which increased significantly to 31.1% after commencement of clozapine treatment. Among the 53 patients without baseline ECG abnormalities, 13 showed new-onset ECG abnormalities after using clozapine. Normal ECG under previous antipsychotic medication reduced the risk of new-onset ECG abnormalities, whereas increased age was found to increase the risk. The occurrence of orthostatic hypotension or tachycardia was not related to the development of ECG abnormalities. Most of the newly developed abnormalities had little clinical significance, and they tended to occur during the initial phase of treatment. In 10 patients, ECGs normalized despite the continued use of clozapine. Clozapine increased corrected QT interval (QTc) in a dose-dependent fashion; however, the clinical significance of this observation is uncertain. Pathologic prolongation of QTc was found to be rare. CONCLUSION: Although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.

Adolescent↗

PubMed2000

Decreased oral bioavailability of loxoprofen at second administration in human subjects.

The objective of this study was to determine the extent of period effect on the pharmacokineitcs of loxoprofen during consecutive dosing. Loxipen and Loxonin tablets were administered to 16 healthy Korean male subjects at a single dose of 60 mg as loxoprofen sodium anhydrous in a 2 x 2 crossover investigation with a two-week wash-out phase. Concentrations of loxoprofen in plasma were measured by HPLC method for 6 h. The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there was a significant (p < 0.05) period effect in AUCinf (area under the plasma concentration-time curve from time zero to infinity) between the administrations. A 20% decrease in the AUC was seen at the second administration. This period effect on pharmacokinetics of loxoprofen may be relevant for the patients who need consecutive administration of the drug.

Administration, Oral↗

PubMed1999

Future drug delivery research in South Korea.

According to the Science Citation Index database, over 50 papers related to drug delivery have been published from South Korea during the last 3 years. For the purpose of this presentation, some of the recently carried out research in our department will be introduced and future research directions presented. Proliposomes are free flowing particles which are composed of drugs, phospholipids and a water soluble porous powder, and immediately form a liposomal dispersion upon hydration. The preparation can be stored sterilized in a dried state and, by controlling the size of the porous powder in proliposomes, relatively narrow range of reconstituted liposome size can be obtained. Because of these properties, proliposomes appear to be a potential alternative to liposomes in design and fabrication of liposomal dosage forms. Thus, we tested the feasibility of this preparation as a sustained transdermal dosage form. Proliposomes containing varying amount of nicotine, a model drug, were prepared using sorbitol and lecithin. Microscopic observation revealed that this preparation is converted to liposomes almost completely within minutes following contact with water. The release pattern of the model drug from this preparation was apparently similar to that of the Exodus((R)) patch, a commercially available transdermal nicotine formulation. Compared with nicotine powder, the nicotine flux across rat skin from proliposomes was initially retarded, and appeared to remain constant. This observation indicated that sustained transdermal delivery of nicotine is feasible using proliposomal formulations under occluded condition. In addition to the investigation of the potential application of proliposomes, we were also interested in the role of the stratum corneum (SC) in the enhanced delivery of drugs from liposomes. Thus, liposome-gel formulation containing hydrocortisone (HC), a model hydrophobic drug, was prepared and used in this study. The study was carried out on both normal and stratum corneum removed skins. Percutaneous absorption of HC across SC removed skin was significantly faster than that across normal skin, suggesting that SC behaves as a penetration barrier for the liposome-bound drugs. Interestingly, the liposome-gel in this study reduced the skin absorption of HC, compared with the conventional ointment formulation. The amount of HC absorbed from the liposome-gel after 8 h into the SC-removed skin was less than one third of that from the conventional ointment. Despite the reduced absorption, a higher and sustained skin concentrations of HC were achieved for the liposome-gel. Drug concentration in both viable and deep skin reached a maximum within 0.5 h. However, drug concentrations in these tissues declined as a function of time for conventional ointment, while those from the liposome-gel were greatly sustained, resulting in a 5-fold higher viable skin drug level was obtained at 8 h after the application. In contrast, plasma concentration of HC at 4 h from the liposome-gel was only one-fourth the value from the conventional ointment in the SC-removed skin. Therefore, the higher and sustained drug concentration in the viable skin appeared not to be due to the enhanced percutaneous absorption but due to retarded diffusion of the drug from the skin.

Animals↗

PubMed1999

Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.

Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.

Adhesiveness↗

PubMed1999

Simultaneous GC-MS determination of nicotine and cotinine in plasma for the pharmacokinetic characterization of nicotine in rats.

A gas liquid chromatography/mass spectrometry assay method was developed for the simultaneous determination of nicotine and its major metabolite, cotinine, in rat plasma. Of particular interest was improving the low and variable extraction recovery for the parent drug and the metabolite. In addition, the feasibility of this assay method for pharmacokinetic studies of nicotine and cotinine after intravenous (i.v.), oral, and intraperitoneal (i.p.) administration of 1 mg kg(-1) of nicotine was tested. The low (30 and 48% for nicotine and cotinine, respectively) and variable (25 and 22% coefficient of variation for nicotine and cotinine, respectively) extraction recovery for nicotine and cotinine into dichloromethane was significantly improved by the addition of NaCl to the plasma. As a result, the recoveries for nicotine and cotinine were improved to 68 and 65%, respectively. The coefficient of variation was less than 10% in the 50-500 ng ml(-1) range and less than 16.58% at 10 ng ml(-1) for both nicotine and cotinine, indicating that the reproducibility of the assay was also improved by the extraction procedure. When injected intravenously at a dose of 1 mg kg(-1), the temporal profile of plasma concentration for nicotine followed a bi-exponential decline. Moment analysis revealed that pharmacokinetic parameters for nicotine (i.e. Cl, 46.30 ml min(-1) kg(-1); Vss, 2.77 1 kg(-1)) was similar to those reported in studies using 14C-nicotine. Absolute bioavailabilities of nicotine for i.p. and oral administration were 87.0 and 80.4%, respectively. The concentration of the metabolite increased up to 4 h to reach Cmax after i.p. and oral administrations and then declined slowly with time. These results indicate that this convenient analytical procedure is readily applicable to pharmacokinetic studies of nicotine and cotinine involving small laboratory animals with a sensitivity comparable with that reported for studies using 14C-nicotine.

Administration, Oral↗

PubMed1999

Selective inhibition of beta-1,4- and alpha-1,3-galactosyltransferases: donor sugar-nucleotide based approach.

A combined rational and library approach was used to identify bisphosphonates (IC50 = 20 microM) and galactose type 1-N-iminosugar (IC50=45 microM) as novel motifs for selective inhibition of beta-1,4-galactosyltransferase (beta-1,4-GalT) and alpha-1,3-galactosyltransferase (alpha-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of beta-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of beta-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors.

Animals↗

PubMed1999

Different activity of ATP dependent transport across the canalicular membrane for tributylmethylammonium and triethylmethylammonium as a potential mechanism of the preferential biliary excretion for tributylmethylammonium in the rat.

PURPOSE: The mechanism(s) responsible for the significantly higher biliary excretion of tributyl methyl ammonium (TBuMA) than of triethyl methyl ammonium (TEMA) was investigated in canalicular liver plasma membrane vesicles (cLPM). METHODS: The uptake of [3H]TBuMA and [3H]TEMA into cLPM in the presence of a pH gradient or ATP was measured by a rapid filtration technique. RESULTS: The uptake of substrates into the vesicle was significantly increased by an outwardly directed pH gradient. The pH dependent uptake was saturable and cross-inhibited by the other organic cation, indicating that TEMA and TBuMA share a common transport mechanism. Kinetic analysis revealed the two compounds show similar characteristics for the pH-gradient dependent uptake. Thus, the organic cation/H+ exchange mechanism does not appear to explain the significant difference in biliary excretion of the organic cations. In the presence of ATP, however, uptake into cLPM was readily observed for TBuMA while TEMA uptake was negligible. Inhibition studies with typical P-glycoprotein substrates indicated the uptake may be mediated by the P-glycoprotein. CONCLUSIONS: Differences between TBuMA and TEMA in reactivity for an ATP dependent transport process, rather than for an organic cation/H+ exchanger, may be responsible for the markedly different biliary excretion of TBuMA and TEMA.

Adenosine Triphosphate↗