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S Melethil

Publications and source records attributed to S Melethil.

33 records · Page 2Linked to original sources
PubMed1987

Pharmacokinetics of gold sodium thiomalate in rabbits.

Male, New Zealand white rabbits (3.5-4.3 kg) received a single 2-mg/kg dose of gold sodium thiomalate (Myochrysine) via intramuscular (N = 4) and intravenous (N = 3) routes. Blood samples were drawn from the marginal ear vein for a period of 5-10 days. The concentration of gold in whole blood was determined using graphite furnace atomic absorption spectrophotometry. The blood concentration-time profiles obtained following both routes of administration were best described by a two-compartment open model with first-order absorption for the intramuscular route. Gold was absorbed rapidly with a mean (harmonic) absorption half-life of 9.0 min, with a peak concentration of 6.0 +/- 1.0 micrograms/ml (N = 4). Blood concentrations declined in a biphasic manner; the mean alpha half-lives were 0.738 and 1.78 hr for the iv and im routes, respectively. The corresponding terminal (beta) half-lives were 54.1 and 63.0 hr. The estimated volume of the central compartment (70 to 93 ml/kg) agreed closely with the rabbit blood volume. The mean (+/- SD) extent of the dose absorbed following intramuscular injection was 68.9 +/- 12.4%.

Animals↗
PubMed1987

Kinetics of potassium excretion following oral supplements: evidence of induced natriuresis.

Twenty-four healthy normal volunteers were given 40 mEq of three oral formulations of K+ as potassium chloride in a three-way Latin square design. Pharmacokinetic characteristics of potassium disposition were determined using urinary excretion data. Potassium was absorbed almost instantaneously from the 10% (w/v) solution, while a slow first-order absorption could explain the slow release of potassium from Slow-K and the new slow-release tablet. A biphasic elimination of potassium observed during the first 24 hr of urinary excretion suggested the body's adaptive process of changes in rates of elimination of potassium to maintain homeostasis. There was no significant difference (P = 0.25) in total recoveries of potassium in urine during 48 hr of urinary collection among the three formulations (mean +/- SE: solution, 35 +/- 7.1 mEq; Slow-K, 38.1 +/- 7.8 mEq; and new formulations, 33.5 +/- 6.8 mEq). An increased excretion of sodium was observed and correlated with increased potassium excretion following oral potassium administration which could not be explained by changes in urine flow rate. The clinical significance of such an increase in natriuresis is yet to be determined.

Administration, Oral↗
PubMed1986

Probenecid disposition by parallel Michaelis-Menten and dose-dependent pseudo-first-order processes.

Re-evaluation of published data on the urinary excretion of probenecid [4-(dipropylamino)sulfonylbenzoic acid, 1] and its metabolites as a function of orally administered dose has revealed that the elimination process is comprised of five parallel pathways. Excretion of the major metabolite, the acyl glucuronide 2 (35-45% of dose), follows Michaelis-Menten kinetics. The three oxidized metabolites, the mono-N-propyl, carboxylic acid, and secondary alcohol derivatives 3, 4, and 5, respectively, (totaling 30% of dose), each adhere to pseudo-first-order kinetics in which the elimination rate constant, as a result of product inhibition, is a function of the administered dose. Four to 13% of the dose is eliminated unchanged in apparent first-order fashion. A mathematical relationship between elimination half-life and dose, under conditions of product inhibition, is derived. Computer simulation of the elimination process confirms the experimental observation that the fraction of dose excreted in the form of each metabolite remains relatively constant over the dose range of 0.5 to 2 g. This study is believed to represent the first application of parallel Michaelis-Menten and dose-dependent pseudo-first-order processes to drug disposition. It demonstrates that the observation of constant proportions of excreted metabolites over a relatively wide range of doses does not provide evidence that the elimination process remains first-order.

Dose-Response Relationship, Drug↗
PubMed1984

Effect of oxygen-carrying resuscitation fluids on the pharmacokinetics of antipyrine, diazepam, penicillin, and sulfamethazine in rats.

The effects of exchange transfusion with an oxygen-carrying resuscitation fluid, Fluosol DA 20% or stroma-free hemoglobin, on the pharmacokinetics of antipyrine, diazepam, penicillin, and sulfamethazine were studied in rats. After transfusion with Fluosol DA 20% or stroma-free hemoglobin the pharmacokinetics of antipyrine, diazepam, and penicillin were unchanged when compared to control animals. After transfusion with Fluosol DA 20%, the t 1/2 of sulfamethazine was increased from 3.15 +/- 0.56 to 7.65 +/- 2.41 hr (p less than 0.05) and the Vd was increased from 60.7 +/- 17.5 to 152 +/- 16 ml (p less than 0.05). In contrast, after transfusion with stroma-free hemoglobin, the AUC of sulfamethazine was decreased from 129 +/- 28 to 80.5 +/- 27.7 micrograms X h X ml-1 (p less than 0.05) and there was an increase in Cl from 12.2 +/- 3.4 to 20.2 +/- 6.0 ml X h-1 (p less than 0.05) and Vd from 60.1 +/- 11.8 to 132 +/- 49 ml (p less than 0.05). The reason for these alterations is not clear. Fluosol DA 20% and stroma-free hemoglobin may alter the acetylation of sulfamethazine.

Animals↗
PubMed1983

The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis.

We examined theophylline pharmacokinetics for changes caused by the addition of erythromycin in patients with chronic bronchitis and obstructive pulmonary disease. Twelve hospitalized patients were randomized in a crossover fashion to receive aminophylline and either erythromycin or placebo. After the eighth dose, plasma was analyzed for theophylline, using the enzyme-mediated immunoassay technique. A 6-h urine collection was analyzed for theophylline metabolites, using high-pressure liquid chromatography. Erythromycin significantly decreased mean theophylline clearance by 22% from 4.9 L/min to 3.87 L/min (p less than 0.05). Mean peak theophylline levels increased 28% from 11.9 micrograms/ml to 15.3 micrograms/ml (p = 0.05). No change in urine theophylline metabolites was found. Patients with chronic bronchitis and obstructive pulmonary disease who begin erythromycin while receiving a preexisting therapeutic theophylline regimen experience a significant elevation of theophylline concentration, which predisposes to theophylline toxicity. For those patients with theophylline levels at the higher end of the therapeutic range (15 to 20 micrograms/ml), we recommend an initial 25% reduction in theophylline dosage when erythromycin is added. Serum theophylline levels should be monitored for further refinement of dosage.

Adult↗
PubMed1982

Steady state urinary excretion of theophylline and its metabolites in the presence of erythromycin.

The effect of erythromycin on the quantitative pattern of urinary excretion of theophylline and its known metabolites at steady state in eight human subjects was examined. The percent of dose excreted of the various compounds in the absence and presence of the antibiotic were as follows: theophylline, 9.3% vs. 16.3%; 1, 3-dimethyluric acid, 51.9% vs. 59.6%; 3-methylxanthine, 11.9% vs. 13.0%; and 1-methyluric acid, 27.3% vs. 31.6%. These results show that erythromycin did not influence the metabolism of theophylline under the experimental protocol employed.

Adult↗
PubMed1981

Estimation of the amount of drug absorbed in acetaminophen poisoning: a case report.

A case of acute acetaminophen overdose has been presented in which good agreement between the observed and the calculated urinary excretion of acetaminophen was obtained using the pharmacokinetic model of Prescott et al (1). This case exemplifies the application of pharmacokinetic principles in the determination of the actual amount of drug absorbed in instances of drug overdose.

Absorption↗
PubMed1980

Binding of gold to bovine serum albumin using flameless atomic absorption.

A graphite furnace atomic absorption spectrophotometric assay capable of accurately determining nanogram amounts of gold in biological fluids was developed. The presence of bovine serum albumin and/or phosphate in the sample reduced the method sensitivity without affecting the linear response. Binding of gold was studied by ultrafiltration using cones with a molecular weihght cutoff of 25,000. The binding of gold at various concentrations to 2 and 4% bovine serum albumin in 0.1 M phosphate buffer, pH 7.4, was independent of the gold and protein concentrations. In the 2-10 microgram/ml range, the overall binding values (mean +/- SD) of gold to 2 and 4% bovine serum albumin were 98 +/- 1.6 (n = 35) and 99 +/- 1.0% (n = 15), respectively. When ultrafiltration cones with a molecular weight cutoff of 50,000 were used, the extent of binding to 2% bovine serum albumin was 85.4 +/- 1.6% (n=11). This statistically significant difference (p less than 0.001) was due to variations in the protein retention of the two cone types. Interaction studies showed that gold was not displaced from the binding sites by salicylic acid (200 microgram/ml) or vice versa.

Animals↗
PubMed1976

Urinary excretion of probenecid and its metabolites in humans as a function of dose.

A GLC assay was used to study the excretion of probenecid and its metabolites in the urine of human subjects following oral doses of 0.5, 1, and 2 g. From 75 to 88% of the dose was found in the urine. The major metabolite, probenecid acyl glucuronide, accounted for 34-47% of the dose. Approximately equal amounts (10-15%) of the mono-N-propyl, secondary alcohol, and carboxylic acid metabolites were excreted in the unconjugated from with only traces in the conjugated form. The primary alcohol metabolite was not found in measurable amounts. The terminal half-lives for excretion of all metabolites were in the range of 4-6 hr, were independent of dose, and were limited by their rates of formation. A prolonged time course of excretion of the metabolites, particularly at higher doses, suggests that probenecid, being poorly soluble in water, precipitates from solution in the GI tract, forming a depot of drug from which absorption is dissolution rate limited. The urinary excretion of unchanged probenecid, which accounts for 4-13% of the dose, is dependent on both the pH and flow rate of urine.

Adult↗
PubMed1976

Comparative pharmacokinetics of cefamandole, cephapirin, and cephalothin in healthy subjects and effect of repeated dosing.

Cefamandole nafate, cephapirin, and cephalothin were administered intravenously in crossover fashion to 12 volunteers, in dosages of 2 g every 6 h for 16 doses. Mean peak levels of cefamandole were approximately 50% higher than those of the other agents. The serum concentration curves appeared to decline bi-exponentially, suggesting that a two-compartment model was most applicable for pharmacokinetic analysis; accordingly, the t((1/2)) of cefamandole was significantly longer when the serum peak was omitted from the analysis (0.86 versus 0.73 h, P < 0.05). The half-lives of cephalothin and cephapirin, 0.34 and 0.36 h, respectively, were probably underestimates reflecting the inclusion of distribution-phase values in the calculation. Repeated dosing had no effect on the peak serum levels, half-life, serum clearance, or apparent volume of distribution with one exception: peak serum levels of cephapirin were significantly lower after the sixteenth than after the first dose. Marked variations within a given subject were noted in the half-life and apparent volume of distribution of cefamandole in several instances. Renal clearances of cefamandole exhibited saturation kinetics similar to those of penicillin G.

Cephalosporins↗
PubMedDate not supplied

The disposition and elimination of stereoisomeric pairs of thioridazine 5-sulfoxide in the rat.

The disposition and elimination of 2 stereoisomeric forms of thioridazine 5-sulfoxide (ring sulfoxide) were followed for 72 hr in male Sprague-Dawley rats following the administration of a single 40 mg/kg intraperitoneal dosage. The distribution half-lives for the fast (RSF) and slow (RSS) eluting ring sulfoxides in serum were 4.40 and 3.23 min, respectively. Elimination half-lives were 1.79 and 2.06 h. Both RSF and RSS were distributed throughout the tissue in equal amounts based on HPLC analysis of the tissues. Both isomers were found in lung tissue at concentrations 10 times that for other organs. Elimination of the ring sulfoxide was complete by 72 hours except in the brain, lung and kidney. The brain, heart, liver and kidney exhibited periodicity, or recycling of both RSF and RSS during the elimination phase. Release of RSF and RSS from myocardial tissue was slower than that for all other tissues. Excretion of unchanged thioridazine 5-sulfoxide occurred via renal, and to a lesser extent, biliary mechanisms. The biliary excretion pattern suggested an enterohepatic circulation of both isomers. These results indicate a lack of stereoselectivity in the disposition and clearance of the two ring sulfoxide isomers in the animal model; results that mirror those seen in man.

Animals↗
PubMedDate not supplied

Effect of sucralfate on phenytoin bioavailability.

The mechanism of action of the antiulcer agent, sucralfate, involves drug binding to proteins, pepsin, and bile salts. The potential for sucralfate to bind to, and inhibit the oral absorption of, concurrently-administered drugs has been studied for very few agents. Phenytoin bioavailability was studied following a single dose of phenytoin 500 mg po in nine normal subjects during a control period and when given with sucralfate. Area under the serum concentration-time curve was compared at 48 hours (AUC48) and 120 hours (AUC120) using observed and extrapolated data. The phenytoin AUC48 was reduced from 173.6 +/- 22.6 mg . h/L to 157.1 +/- 19.6 mg . h/L (p less than 0.02), and the phenytoin AUC120 was reduced from 200.5 +/- 31.9 mg . h/L to 185.0 +/- 26.8 mg . h/L (p less than 0.05), when sucralfate was administered. Because AUC comparisons for drugs with nonlinear elimination kinetics may reflect changes in rate, as well as extent, of absorption, these small changes in AUC may not reflect a change in the fraction of dose absorbed. However, our results suggest that sucralfate does affect phenytoin absorption. Further studies may be useful in determining the precise nature and clinical importance of this interaction.

Adult↗