Determination of theophylline in plasma by electron capture gas chromatography.
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Chromatography, Gas↗
Biomedical subjects
T M Ludden
Publications and source records attributed to T M Ludden.
Metabolic reduction of naltrexone II. In vitro studies using liver from guinea pig, monkey and rat.
Naltrexone was incubated with the 9000 X g supernatant of guinea pig liver in the presence of an NADPH-generating system to determine the relative amounts of the 6-keto reduction products, alpha- and beta-naltrexol, formed in vitro. After a 0.5-2 hour period both alpha- and beta-naltrexol were formed as detected by electron capture gas chromatography of pentafluoropropionic anhydride-derivatized extracts of the incubation mixture. The identity of alpha-naltrexol was confirmed by nuclear magnetic resonance, infrared and mass spectra, as well as by mixed melting point determination. The percentage of natrexol found as the alpha-epimer ranged from 36-81% and was concentration-dependent at substrate concentrations ranging from 0.0007-0.1 mM. The hepatic enzyme(s) responsible for the reduction of naltrexone were localized in the 105,000 X g supernatant fraction of guinea pig liver. In contrast to results obtained for the reduction of naltrexone using guinea pig liver, the 9000 X g and 105,000 X g supernatant fractions of monkey liver appeared to reduce naltrexone almost exclusively to beta-naltrexol. The 9000 X g supernatant of rat liver was less active than similar preparations from guinea pig or monkey liver; only a small amount of beta-naltrexol and no detectable alpha-naltrexol was formed after two hours of incubation. Incubation of the naltrexone metabolites, alpha- or beta-naltrexol, with the 9000 X g supernatant of guinea pig liver and incubation of alpha-naltrexol with guinea pig kidney slices yielded no evidence of interconversion of these metabolites.
Animals↗
Metabolic reduction of naltrexone. I. Synthesis, separation and characterization of naloxone and naltrexone reduction products and qualitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or beta-naltrexol.
Reduction of naltrexone and naloxone with sodium borohydride gave a mixture (85:15) of the 6alpha- and 6beta-hydroxy epimers, alpha- and beta-naltrexol and alpha- and beta-naloxol, respectively. Each pair of epimers was separated by preparative thin-layer chromatography and the physical and spectral properties of each compound were determined. Previous assignments for the configuration of the epimers were verified. A semi-quantitative electron capture gas-liquid chromatographic method was devised for distinguishing either alpha- or beta-naltrexol in the presence of the other and in the presence of large amounts (at least 10-fold greater) of naltrexone. The method was used to determine the approximate weight ratio of beta-naltrexol to naltrexone present in enzymatically hydrolyzed urine samples. It was found that substantially greater quantities of beta-naltrexol and/or its conjugates were excreted in the urine of man, monkey, guinea pig and rabbit after administration of naltrexone, whereas very small quantities were excreted by the mouse, rat and dog. In contrast, just trace amounts of the 6alpha-hydroxy epimer, alpha-naltrexol, were detected in the urine of only 2 of the 7 species that had received naltrexone, i.e., monkey and guinea pig. After administration of 3H-15,16-naltrexone, 1 mg/kg, i.v. to the guinea pig, 25% of the radioactivity found following thin-layer chromatography of the extract of acid-hydrolyzed urine corresponded to beta-naltrexol. In gall bladder bile from the guinea pig, only conjugates of naltrexone and beta-naltrexol were found 2 hours after administration of naltrexone. Following administration of beta-naltrexol, 1 mg/kg, i.v. to guinea pigs only beta-naltrexol and/or its conjugates were detected in urine or bile. However, urine collected after administration of alpha-naltrexol, 1 mg/kg, i.v. to guinea pigs contained alpha-naltrexol and its conjugates, as well as a yet unidentified metabolite.
Animals↗
Procainamide accumulation kinetics in the immediate postmyocardial infarction period.
The rate of change of plasma procainamide concentration during 36 hours of constant-rate intravenous infusion was examined in five acute myocardial infarction patients. It was observed that a steady-state plasma concentration was established in about 16 hours, which is consistent with simulations of plasma concentrations based on pharmacokinetic constants obtained from studies in young healthy volunteers. However, the steady-state level that was attained in these patients was markedly higher than that which the simulations predicted. Thus, on the average, acute myocardial infarction patients have lower total body clearances of procainamide than normal volunteers.
Adult↗
Rapid establishment of therapeutic serum concentrations of salicylates.
A minimum serum salicylate concentration of 150 microgram/ml is required to control certain inflammatory disease processes. A loading regimen designed to rapidly achieve this minimal level was evaluated in six normal volunteers (age 22 to 27 years, weight 70.5 to 84.1 kg) using a randomized crossover design. The control group received 650 mg aspirin (ASA) every 4 hours for 48 hours. The loading regimen was 2600 mg ASA divided into two equal doses 4 hours apart. Maintenance dosing of 650 mg ASA every 4 hours was then started 4 hours after the completion of the loading regimen and continued for 40 hours. Serum samples were drawn at 0, 2, 4, 6, 8, 12, 24, 36, and 48 hours after initiation of the study and were assayed for salicylate concentration by UV spectrophotometry. Loading with aspirin produced serum concentrations which were significantly higher (P less than 0.01) for the first 24 hours and reduced the time to reach 150 microgram/ml (15.3 +/- 5.9 hours versus 30.4 +/- 8.65 hours, P less than 0.001) for five of six subjects when compared to a conventional regimen. One subject did not achieve 150 microgram/ml at 48 hours with either regimen. Considerable intersubject variation in serum concentration was noted at 48 hours for both regimens. We suggest that a loading regimen for aspirin may have utility for patients in whom rapid attainment of a therapeutic antiinflammatory serum concentration is desirable.
Adult↗
Bupivacaine and other amide local anesthetics inhibit the hydrolysis of chloroprocaine by human serum.
The rate of hydrolysis of chloroprocaine by human serum was studied in the presence and absence of a number of aminde local anesthetics and their metabolites. Bupivacaine (2.4 microgram/ml) and etidocaine (2.3 microgram/ml) caused 38% and 21% inhibition respectively of the rate of chloroprocaine hydrolysis. Circulating concentrations of these drugs have been reported in this range by several investigators following epidural doses of 150 to 400 mg of either drug. Mepivacaine, lidocaine, and two lidocaine metabolites (glycine xylidide and monoethylglycine xylidide) were only inhibitory at levels much greater than those seen in blood following the usual local anesthetic doses of the parent compounds. Since serum is an important site of chloroprocaine metabolism in man, the probability of chloroprocaine intoxication may be increased when it is administered with local anesthetics such as bupivacaine and etidocaine.
Anesthetics, Local↗
Elimination of radioactivity following administration of [15,16-3H]naltrexone to rats and guinea pigs.
The elimination of radioactivity after [15,16-3H]naltrexone administration was studied in rats and guinea pigs. An average of 42% of the dose was eliminated in urine and 55% in feces following administration of 1 mg/kg iv to each of three rats. Analysis of radioactivity in the excreta of one rat that received the same dose im yielded similar results. On the other hand, four guinea pigs that received 1 mg/kg iv excreted only 14% of the dose in feces and 84% in urine. Similar results were obtained following im administration to guinea pigs at 1 and 20 mg/kg doses. In guinea pig excreta, an average of 64% of the dose corresponded to naltrexone and conjugates, 19% to beta-naltrexol and conjugates, and 2% to alpha-naltrexol and conjugates. In urine, the radioactivity corresponding to alpha-naltrexol and naltrexone was present mainly in conjugated form, whereas apparent beta-naltrexol was mainly unconjugated. The radioactivity in feces corresponded principally to unconjugated naltrexone and beta-naltrexol.
Animals↗
Binding of organic compounds to rat liver and lung.
The binding of various radioisotopically labeled organic compounds to rat liver and lung was investigated in vitro. Pieces of rat lung and slices of rat liver were incubated at 37 degrees C under a nitrogen atmosphere in a modified Krebs-Ringer phosphate solution (pH 7.4) CONTAININg the compound to be studied. Of the neutral compounds investigated, digitoxin, digoxin and dexamethasone were highly bound to both liver and lung tissue, whereas the degree of binding of amitrole, erythritol, and ouabain was 20% or less. The weak acids which were bound to the greatest extent in both liver and lung were phenobarbital, pentobarbital, and diphenylhydantoin. Barbital was poorly bound, and there was no evidence for the binding of 5,5-dimethyloxazolidine-2,4-dione or p-aminohippuric acid in either tissue. Binding of the cardiac glycosides and the barbiturates directly paralleled their lipid solubilities. The degree of binding of neutral compounds and weak acids to lung and liver tissue did not vary greatly with concentration, even though broad concentration ranges were studied. This was also true of the weak base morphine. On the other hand, the binding to liver and lung of the organic bases nicotine, pilocarpine, d-amphetamine, lidocaine, erythromycin, and chloroquine, did vary with concentration. The quaternary ammonium compound decamethonium was bound only to liver, and this binding also varied with concentration. Two additional quaternary ammonium compounds, tetraethylammonium and N1-methylnicotinamide, were not significantly bound to either tissue. Comparisons on the basis of equal content of solids revealed that the binding of diverse organic compounds in liver is greater than or equal to that in lung.
Amitrole↗