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Biomedical subjects

E T Lin

Publications and source records attributed to E T Lin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Food intake and dosage level, but not tablet vs solution dosage form, affect the absorption of metformin HCl in man.

The pharmacokinetics of four single-dose treatments of the metformin administered orally (as the HCl salt) were compared in 24 healthy subjects: 500 mg and 850 mg tablets and 850 mg solution fasting and 850 mg tablet with food. Solution and tablet formulations are bioequivalent. Bioavailability of a 500 mg tablet is 14% greater than that of an 850 mg tablet. Compared with the fasting state, bioavailability is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food.

Adult↗
PubMed1996

Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCL (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCL (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Adult↗
PubMed1995

Kidney function and age are both predictors of pharmacokinetics of metformin.

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CL*cr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CL*cr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.

Adult↗
PubMed1995

Propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Propranolol pharmacokinetics among different genotypes of CYP2D6 was compared in this study. The Chinese (Han) population consisted of 44 healthy unrelated individuals living in southern Taiwan. Endonuclease tests based on polymerase chain reaction were used to determine C/T188 genotypes of CYP2D6 in leukocyte deoxyribonucleic acid. Based on codon 188 genotypes, subjects were categorized into three groups: homozygous C/C188 (n = 13), heterozygous C/T188 (n = 14); and homozygous T/T188 (n = 17). Each subject was given a 40 mg propranolol tablet. Blood samples were drawn before and 12 hours after propranolol administration to measure propranolol and 4-hydroxypropranolol. Three genotypes showed distinct time profiles of plasma propranolol and 4-hydroxypropranolol. The area under plasma concentration curve values (mean +/- SEM), were 322.0 +/- 40.8, 481.6 +/- 77.5, and 766.1 +/- 92.8 nmol.hr/L, respectively, for C/C188, C/T188, and T/T188 subjects (p < 0.05). The 48-hour excreted amount of 4-hydroxy-S-propranolol-O-glucuronide, but not 4-hydroxy-R-propranolol-O-glucuronide, was significantly higher for C/C188 than for T/T188 subjects (p < 0.05). This study shows a different propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Adrenergic beta-Antagonists↗
PubMed1995

Determination of ticarcillin in human plasma and in urine by reversed-phase LC.

A liquid chromatographic assay for ticarcillin (ticar.) in plasma and urine is described. For analysis, the internal standard cefoperazone (cfp) is dissolved in acetonitrile, which is used for precipitating the protein. The supernatant is evaporated, reconstituted in running mobile phase and injected directly onto the reversed-phase C18 column, with detection at 205 nm. The mobile phase is composed of water-acetonitrile-o-phosphoric acid-tetramethylammonium chloride (TMA). Coefficients of variation for reproducibility were in the range of 2.2-15.5% for extra-low, low, medium and high controls. Limits of detection were 0.5 microgram ml-1 for plasma and 1 microgram ml-1 for urine. No interference from other cephalosporins or other antibiotics was noted. This liquid chromatographic assay is simple, accurate, requires no extraction and overcomes previous problems related to the drug's peak splitting due to isomerization.

Calibration↗
PubMed1995

Apparent intramolecular acyl migration and hydrolysis of furosemide glucuronide in aqueous solution.

The stability of furosemide glucuronide (FG) was investigated in buffer solutions ranging from pH 1 through 10. This glucuronic acid conjugate was the major metabolite of furosemide (F) excreted in human urine. FG, obtained by extraction from human urine, was purified by ion-exchange chromatography. The concentration of FG, acyl migration isomers of FG (FG-iso), and F were determined simultaneously with an HPLC method that included fluorescence detection and gradient elution. FG was found to be unstable in highly acidic and in neutral to alkaline solutions. Hydrogen ion and hydroxy ion catalyzed the hydrolysis of FG below pH 2.8 and above pH 5.6, respectively. Above pH 3.7, FG instability led to the formation of eight FG-iso compounds. Though beta-glucuronidase cleaved FG, the FG-iso compounds were resistant to the enzyme. The half-life of FG in a buffer solution at pH 7.4 and 37 degrees C was 4.4 h. The maximum stability of FG (half-life about 62 d) occurred at approximately pH 3.2. Below pH 3.7, acyl migration products of FG were not detected. Instead, the hydrolysis of FG to F and glucuronic acid was followed by the formation of 4-chloro-5-sulfamoylanthranilic acid (CSA), a secondary product in acidic media.

Acylation↗
PubMed1995

Biliary excretion of furosemide glucuronide in rabbits.

Furosemide (F) was administered to rabbits intravenously and intraduodenaly and the biliary excretion was studied. The major metabolite excreted in bile was furosemide glucuronide (FG). F and acyl migration isomers of FG (FG-iso) were also excreted in bile. The biliary excretion rates of total F (F+FG+FG-iso) following intraduodenal administration of F were much smaller than those following intravenous administration. The fraction of (F+FG-iso) in bile following intraduodenal administration of F were larger than those following intravenous administration. Stability of FG or FG-iso in bile and supernatant solution of the duodenum homogenate of rabbits was studied. FG was unstable in both media and its degradation followed apparent first-order kinetics in both media. In bile, FG degraded to produce several FG-iso and F, while in the supernatant solution of the duodenum homogenate, it hydrolyzed immediately to F. FG-iso were hardly detected in the supernatant solution. These results indicated that FG excreted in bile degraded easily to FG-iso and F. FG might easily hydrolyze to F enzymatically in the duodenum, and the resultant F might be reabsorbed from the intestinal tract. Unabsorbed FG-iso and F might be excreted in the feces.

Adult↗
PubMed1995

Pre-column fluorescence derivatization using leucine-coumarnylamide for HPLC determination of mono- and dicarboxylic acids in plasma.

A sensitive HPLC assay utilising a simple fluorescence pre-column labelling technique was developed for plasma level monitoring of different types of mono- and dicarboxylic acids. Carboxylic acids form mixed anhydrides with ethyl chloroformate in the presence of triethylamine; the mixed anhydrides further react with L-leucine-4-methyl-7-coumarinylamide, forming highly fluorescent and stable amides. Drugs with no chromophore (azelaic acid, and its longer carbon chain analogues) or week UV absorption (artelinic acid, enalaprilat) were used as model compounds. The plasma samples were extracted using ion exchange solid phase cartridges. The separation was performed on an Axxiom C18 (5 microns, 4.6 x 250 mm) column. The detector wavelengths were set at 330 nm for excitation and 390 nm for emission.

Animals↗
PubMed1994

Simultaneous measurement of nicotinic acid and its major metabolite, nicotinuric acid in urine using high-performance liquid chromatography: application of solid-liquid extraction.

The concentrations of nicotinic acid (NiAc) and nicotinuric acid (NiUAc), a major metabolite of NiAc, were simultaneously determined in urine using solid-phase extraction (cation-exchange extraction) and reversed-phase high-performance liquid chromatography with ultraviolet detection. The intra- and inter-day precision studies showed good reproducibilities: the coefficients of variations were less than 8.1% for NiAc and 8.8% for NiUAc. The calibration curves were linear (r2 > 0.9934) in the concentration range 10-1000 micrograms/ml. The removal of endogenous interferences in urine by solid-phase extraction presented here is superior to the pretreatment protocols reported previously by other workers. The method was used in a preliminary pharmacokinetic study in rats after intravenous administration of NiAc (5 and 15 mg/kg).

Animals↗
PubMed1993

Predictability of the covalent binding of acidic drugs in man.

Although metabolism via glucuronide conjugation has generally been considered a detoxification route for carboxylic acids, the newly discovered chemical reactivity of these conjugates, leading to covalent binding with proteins, is consistent with the toxicity observed for drugs containing the carboxylic acid moiety. Here we report that degradation rates (intramolecular rearrangement and hydrolysis) for 9 drug glucuronide metabolites show an excellent correlation (r2 = 0.995) with the extents of drug covalent binding to albumin in vitro. Furthermore, this binding capacity is predictable based on chemical structure of the acid and depends on the degree of substitution at the carbon alpha to the carboxylic acid. The in vivo covalent binding in humans for these drugs is also predictable (r2 = 0.873) when the extent of adduct formation is corrected for the measured plasma glucuronide concentrations. These results suggest that the structure of a carboxylic acid drug may predict the degree to which the corresponding acyl glucuronides will form covalent adducts that probably/possibly lead to toxicity. This information could be a useful adjunct in drug design.

Animals↗
PubMed1992

Ofloxacin in human serum, urine, and tear film after topical application.

We evaluated the systemic absorption of ofloxacin eyedrops in humans and their availability in the tear film. Serum, urine, and tear film concentrations of ofloxacin were measured in 30 healthy women topically treated with 0.3% ofloxacin, in both eyes, four times daily for 10 1/2 days. Serum was collected before the first daily dose on days 1 and 11 and at 18 time points before the second dose. Maximum serum ofloxacin concentrations (1.89 +/- 1.13 ng/ml) after 10 1/2 days of topical dosing were more than 1,000 times lower than those reported after standard oral doses of 300 mg ofloxacin. Urine was collected for the 24-h period after the first daily dose on days 1 and 10. Topical ofloxacin was excreted in the urine primarily in unmodified form and recovery rates were significantly higher on day 10 (76.1 +/- 41.5%) than on day 1 (56.6 +/- 31.6%) (p less than 0.05). Both serum and urine data give evidence to accumulations of ofloxacin over a 10 1/2-day period. The low serum concentration at steady state suggests an extremely low potential for producing systemic effects. No systemic side effects attributable to topical ofloxacin were observed. Mild ocular irritation was reported by two patients while under treatment. Tears were collected 4 h after the first treatment on day 11 and at 5, 10, 20, 30, and 40 min after the second treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Development of a new controlled-release formulation of chlorpheniramine maleate using in vitro/in vivo correlations.

Development of a controlled-released formulation of chlorpheniramine maleate is described, using in vitro/in vivo correlates, according to a process that has been termed "biorelevant dissolution". The process begins with simulations using several possible input rates combined with known disposition parameters of chlorpheniramine maleate. Based on desired plasma concentrations, an input rate is selected for further development which consists of a combination of clinical bioequivalence studies and further in vitro testing and simulations. The method is designed to reduce the requirements for trial and error clinical bioequivalence testing of a new controlled-release formulation.

Administration, Oral↗
PubMed1991

Nitroglycerin absorption from transdermal systems: formulation effects and metabolite concentrations.

We recently compared plasma concentrations of nitroglycerin and its two dinitrate metabolites in 16 healthy male subjects after application of two controlled-release transdermal formulations of the drug. Analysis of the resulting plasma concentration-time curves indicated that the two formulations did not produce equivalent concentrations of parent drug or either of the dinitrate metabolites during the initial period of dosing. In addition, both formulations produced concentrations of the two dinitrate metabolites that exceeded the concentration of the parent drug by severalfold. Even if the pharmacologic effect of the dinitrate metabolites is low compared to that of nitroglycerin, these higher concentrations may contribute to the effect of nitroglycerin. Scrutiny of the ratio of 1,2-glyceryl dinitrate to 1,3-glyceryl dinitrate in the 16 subjects confirmed previous observations that preferential formation of the 1,2-glycerol dinitrate metabolite may occur depending on the route of administration. This ratio may thus be indicative of the bioavailability of nitroglycerin following transdermal application. Additional data suggesting racial differences in nitroglycerin absorption after transdermal application are presented.

Administration, Cutaneous↗
PubMed1990

Stereoselective binding of the glucuronide conjugates of carprofen enantiomers to human serum albumin.

The stereoselective binding of carprofen enantiomers and carprofen glucuronide diastereomers to human serum albumin (HSA) was studied using an ultrafiltration method. Carprofen glucuronides exhibit a considerable and stereoselective affinity to HSA, although less than that seen for the parent enantiomers. The (S)-glucuronide showed a higher binding affinity to HSA than the (R)-glucuronide. The (S)-enantiomer of unmetabolized carprofen was bound to fatty acid free HSA to a much greater extent than the (R)-enantiomer. Warfarin reduced the binding of the glucuronides to a greater extent than did diazepam, but diazepam displaced the unconjugated enantiomers to a greater extent than did warfarin. These results suggest differences in binding region between the carprofen enantiomers and their glucuronides on the albumin molecule.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Absorption and disposition of a new low-dose combination formulation of hydrochlorothiazide and triamterene.

Two studies are reported that assess the bioequivalence of a new half-strength drug combination containing 25 mg hydrochlorothiazide and 37.5 mg triamterene compared to a full-strength formulation containing 50 mg hydrochlorothiazide and 75 mg triamterene. The first study (I) compared the absorption and disposition of the two drugs after administration of two tablets of the half-strength product as a single dose compared to a single dose of the full-strength product. The second study (II) assessed the bioavailability of the new product given as a single tablet on two occasions separated by an interval of 12 h compared to the full-strength product given as a single dose. Urine parameters in the first study indicated bioequivalence of the half-strength to the full product for both rate and extent of absorption. When given in divided doses, the half-strength product demonstrated bioequivalence to the full-strength product for extent of absorption. Additional data from the second study suggest that absorption of triamterene is greater when given in smaller divided doses and when given at night.

Biological Availability↗
PubMed1990

Pharmacokinetics of nitroglycerin and its dinitrate metabolites over a thirtyfold range of oral doses.

The pharmacokinetics of nitroglycerin and the formation of its dinitrate metabolites (1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate) were determined in six healthy volunteers after administration of six oral solution doses ranging from 0.4 mg to 13 mg. ANOVA analysis indicated significant differences between subjects for all Cmax/dose and AUC/dose measurements. No significant difference between doses were noted for these parameters except for AUC/dose for 1,3-glyceryl dinitrate. The ratio of metabolites (1,2-metabolite/1,3-metabolite) for the 0.4 mg dose was significantly different from the ratios for the doses of 1.6 mg or higher. Measurements of the combined residence time parameter suggest nonlinearity in nitroglycerin absorption and metabolism processes of AUMC/AUC between the 0.4 and the 13 mg doses. Consistent results were observed in the AUC ratios of metabolites for 0.4 mg doses of nitroglycerin between oral and sublingual administrations, suggesting that the increased metabolite ratio noted for sublingual nitroglycerin may reflect differences in dose, rather than differences in route of administration.

Administration, Oral↗
PubMed1990

Supersensitivity to electrical stimulation for assessing physical dependence on opioids in isolated tissues.

The use of the guinea pig ileum (GPI) and mouse vas deferens (MVD) to quantify opiate tolerance and physical dependence in the same preparation was examined. In the GPI, tolerance to and physical dependence on various opiates were induced by direct incubation with an agonist and tolerance and abstinence were assessed after its rapid removal by extensive washing. Dependence, as evidenced by an increase in twitch height and after removal of the agonist as compared to that before incubation, provided an index of the degree of physical dependence. The extent of the supersensitive response after agonist removal was noted to be related directly to the agonist concentration and the degree of tolerance development. Furthermore, the supersensitive response was found to be stereospecific, naloxone reversible and preferentially mu receptor-mediated. Likewise, tolerance to opiates could be demonstrated in the MVD by direct incubation with an agonist. Unlike the GPI, rapid removal of the agonist by washing did not produce a supersensitive response to electrical stimulation. However, a supersensitive response was demonstrable in the presence of naloxone. Thus, after a tolerant/dependent state was induced by incubation of the vas with a predetermined dose of [D-Ala2, D-Leu5]enkephalin that completely abolished the twitch response, the subsequent addition of naloxone resulted in a supersensitive response to electrical stimulation that was concentration-dependent. The maximum twitch response in the presence of naloxone, compared to that obtained before incubation with the agonist, provided an index of the extent of dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗