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Biomedical subjects

D E Duggan

Publications and source records attributed to D E Duggan.

At least 19 recordsLinked to original sources
PubMed1990

High-performance liquid chromatographic determination of cilastatin and its major metabolite N-acetylcilastatin in rat plasma, urine and bile.

A new high-performance liquid chromatographic method coupled with solid-phase (C8) sample extraction has been developed for the simultaneous quantification of cilastatin and its major metabolite N-acetylcilastatin in rat plasma, urine and bile. The method is linear, reproducible and reliable with a detection limit of 1 microgram/ml in all three fluids. Plasma concentrations of cilastatin and N-acetylcilastatin at selected time intervals and biliary and urinary recoveries of cilastatin and N-acetylcilastatin following an intravenous dose of 10 mg/kg cilastatin are presented.

Animals↗
PubMed1987

Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drugs.

The ability of a wide variety of anionic, cationic, and neutral drugs to bind in a reversible manner to plasma proteins has long been recognised. Non-steroidal anti-inflammatory drugs (NSAIDs) are distinguished as a class by the high degree to which they bind to plasma protein. Plasma protein binding properties are primary determinants of the pharmacokinetic properties of the NSAIDs. Theoretical relationships are reviewed in order to define quantitatively the impact of plasma protein binding on clearance, half-life, apparent volume of distribution, and the duration and intensity of pharmacological effect. The quantitative relationships governing competitive displacement binding interactions are also presented. Experimental methods for in vitro and in vivo determination of the degree of plasma protein binding are discussed. The more common in vitro methods are equilibrium dialysis and ultrafiltration. Methods for characterising the degree of plasma protein binding in vivo consist of either measuring the concentration of drug at equilibrium in an implanted semipermeable vessel or measuring the relative drug concentrations in two body spaces with different protein content. Emphasis is given to the comparative advantages and disadvantages of experimental application of the various in vitro and in vivo methods. Plasma protein binding is discussed as a determinant of the trans-synovial transport of NSAIDs. Trans-synovial transport of NSAIDs appears to be a diffusional process. Limited data in humans receiving ibuprofen, indomethacin, aspirin, carprofen, alclofenac, or diclofenac suggest that clearance of each of these NSAIDs from the synovium is slower than clearance from plasma. The clinical data relevant to the relationship between plasma NSAID concentration and various measures of anti-inflammatory effect are reviewed. A positive correlation between plasma NSAID concentration and anti-inflammatory effect has been observed in only one study on naproxen and one study on piroxicam. In several other studies, the lack of concentration-response correlations is generally attributed to the relatively subjective, quantitatively inexact methods used to assess anti-inflammatory effect and analgesia in arthritic patients, as well as the substantial interpatient variabilities in the fraction of unbound NSAID and the unbound plasma NSAID concentration. In view of the generally poor correlation between concentration and therapeutic response, routine therapeutic monitoring of total plasma NSAID concentration is not recommended as a means of titrating individual dosages to the desired effect in each patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats.

The relative contribution of ether and ester glucuronidation to diflunisal metabolism was assessed by studying the effects of enzyme inducers, phenobarbital (PB), 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF). Treatment with either PB, 3-MC or BNF increased markedly the unbound intrinsic clearance of diflunisal. Saline-treated control rats showed a greater unbound intrinsic clearance of diflunisal than oil-treated controls indicating that repetitive treatment with oil had an effect on enzyme activity. Treatment with 3-MC and BNF appeared to cause a decrease in the biliary clearance of ether and ester glucuronide, but PB had little effect on the biliary clearance of glucuronides. Rats pretreated with PB showed a 3-fold increase in the fractional metabolite formation clearance of ether glucuronide and a 2-fold increase in the fractional metabolite formation clearance of ester glucuronide, suggesting differential effects of PB on ester and ether glucuronidation. A similar trend, but to a smaller extent, was also observed for 3-MC- and BNF-treated rats. These results suggest the possibility of selective induction of multiple forms of UDP-glucuronyltransferase involved in metabolism of diflunisal.

Animals↗
PubMed1986

Possible mechanisms for reduced plasma clearance of diflunisal in rat experimental renal failure.

To provide insight into the reported reduction in the plasma clearance of diflunisal in human renal failure, this investigation evaluated several possible mechanisms for this effect in experimental renal failure. Rats with renal failure, induced by uranyl nitrate or by ureteral ligation, had both a lower plasma clearance and an increased apparent volume of distribution, a pattern resembling that seen in human renal failure. Steady-state diflunisal concentration and unbound fraction were determined in studies during a constant infusion of diflunisal to establish the relationships of concentration, protein binding and intrinsic clearance. The infusion studies revealed that the intrinsic clearance of diflunisal, i.e., the ability of enzyme system(s) to metabolize the drug, was decreased in uremia. Also, plasma protein binding of diflunisal was decreased, which may explain the increase in apparent volume of distribution in uremic rats. The decreased intrinsic clearance of diflunisal in uremic rats may be due partly to saturation of biotransformation process(es) by increasing unbound concentration as a consequence of impairment of plasma protein binding of diflunisal, and partly due to the diminished enzyme activity of glucuronidation by renal failure. The lack of an effect of the esterase inhibitor phenylmethylsulfonyl fluoride on the intrinsic clearance of diflunisal in uremic rats suggested that the reduced intrinsic clearance of diflunisal was not attributable to the systemic enzymatic hydrolysis of the ester glucuronide.

Animals↗
PubMed1985

Bioanalysis and disposition of alpha-fluoromethylhistidine, a new histidine decarboxylase inhibitor.

A sensitive, selective, and rapid high-performance liquid chromatographic procedure was developed for the determination of alpha-fluoromethylhistidine (alpha-FMH) in human biological samples. The plasma assay required isolation of the drug using a weak cation-exchange resin prior to HPLC analysis with UV detection. The urine assay employed postcolumn derivatization with o-phthalaldehyde (without a thiol) and fluorescence detection. The extent of metabolism of alpha-FMH in humans was studied in four healthy volunteers using tritium-labeled material. No significant differences in the plasma and urine concentrations of radioactivity and unchanged drug were detected. In addition, the radiochromatograms of selected urine samples revealed a single peak with a retention time corresponding to the unchanged drug. The evidence presented suggests negligible biotransformation of alpha-FMH in humans.

Biotransformation↗
PubMed1985

Dose-dependent pharmacokinetics of diflunisal in rats: dual effects of protein binding and metabolism.

The purpose of this study was to define the dual effects of saturable metabolism and saturable protein binding on the pharmacokinetics of diflunisal. Steady-state diflunisal concentration and its unbound fraction were examined in seven groups of rats to determine the relationships of infusion rate, concentration and total and unbound clearances. The total body plasma clearance decreased initially and then went up as the concentration of diflunisal increased, whereas the intrinsic clearance of unbound drug decreased with increasing concentration. The former is a consequence of saturable metabolism as well as saturable protein binding; the latter is a consequence of saturable metabolism. The fraction of unbound diflunisal increased with concentration. The biliary excretion data of ester and ether glucuronide suggested that both the ester and ether glucuronidation processes are capacity-limited, although the enzyme system for ether glucuronide has a lower Km and capacity than the system responsible for the ester glucuronidation.

Animals↗
PubMed1984

Inhibition of histamine synthesis in vitro and in vivo by S-alpha-fluoromethylhistidine.

(S)-alpha-Fluoromethylhistidine (alpha-FMH) is a Kcat or "suicide-substrate" inhibitor of partially purified mammalian histidine decarboxylase; i.e. the agent is converted enzymatically to a more active form which effects a time-dependent, irreversible inhibition. Incubation of a alpha-FMH[4-3H] with enzyme and pyridoxal phosphate resulted in an apparently irreversible labeling of protein, with no demonstratable formation of free-amine product, suggesting a very low to non-existent turnover ratio. alpha-FMH was accumulated in isolated mastocytoma cells and effected a time-dependent inhibition of the conversion histidine[3H]----histamine[3H], the latter product having a markedly different distribution between cells and medium than the pre-existing histamine pool. Inhibition of whole-body histidine decarboxylase activity, as specifically measured by alpha-methylhistidine-14COOH----14CO2, was also time dependent. Concomitant reduction in histamine levels was seen only in the rapidly turning-over pools of stomach and brain. However, over the course of 13 weeks of chronic treatment, depletion of the relatively inert mast-cell histamine pool(s) was seen as well.

Animals↗
PubMed1984

Sensitive gas-liquid chromatographic procedure for urinary N tau-methylimidazole acetic acid, an index of histamine turnover.

A simple and specific gas-liquid chromatographic procedure, compatible with both nitrogen-phosphorous and electron-capture detection, and employing conventional packed columns, has been devised for urinary 1-methylimidazole-4-acetic acid (N tau-MeImAA), an index of whole-body histamine turnover. N tau-MeImAA is isolated by ion-exchange on Dowex 1 (CH3COO-), esterified by reaction with chloroethanol-boron trichloride and, depending upon detection employed, chromatographed on base-deactivated SP-2401 or SP-2250. [3H]N tau-MeImAA serves as internal recovery standard.

Animals↗
PubMed1983

Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives.

An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.

Alcohol Oxidoreductases↗
PubMed1983

Enterohepatic circulation of sulindac and metabolites.

Four subjects were studied by continuous intraduodenal sampling to establish the existence and determine the extent of enterohepatic recirculation of sulindac and its sulfide and sulfone metabolites. Sulindac, 200 mg by mouth, was given every 12 hr for 7 days. After the last dose was given intraduodenally, constant duodenal infusion of a nutrient mixture and sampling of duodenal contents were performed through a triple-lumen intraduodenal tube for 12 hr. Calculation of nonabsorbed drug in the samples and quantitation of drug and metabolite levels in the biliary secretions were made possible by nonabsorbable markers in the drug solution and in the infusate. Interindividual variations in the absolute values for each of the chemical species were over a 200% range, but for each subject relative clearances were in a remarkably constant ratio, averaging 1:12:12 for sulfide:sulindac:sulfone. Total biliary excretions of the prodrug (sulindac) and active pharmacophore (sulfide) calculated from these biliary clearances and historic mean plasma AUCs were 136% and 22% of dose. Thus, there is a correlation between data in man and those in five other species and the data established that, after sulindac, the contribution of enterohepatic circulation to conservation of the active pharmacophore is achieved predominantly at the level of inactive prodrug.

Adult↗
PubMed1981

Sulindac: therapeutic implications of the prodrug/pharmacophore equilibrium.

Sulindac is a prodrug which, following absorption, rapidly attains a metabolic equilibrium with its active pharmacophore, the sulfide metabolite. At the level of the whole body, the reversible interconversion sulindac in equilibrium sulfide, and the differing distributional and excretory properties of each, provide a theoretical basis for the long plasma half-life of active drug and, in animal species, for the favorable gastrointestinal tolerance observed. In all organ cells examined, and in macrophages, enzyme systems mediating each of the opposing biotransformations between prodrug and active sulfide are present: sulindac reductase in the cytoplasm, and the sulfide oxidase activity in microsomes. Estimated metabolic rate constants for intracellular pools are of the order 0.1-0.3 min-1. It is thus proposed that sulfide, which is oxidized to sulindac in the course of scavenging oxidizing radicals generated in inflammatory responses, may be efficiently regenerated in situ.

Animals↗
PubMed1978

Effects of concomitant aspirin administration on the pharmacokinetics of indomethacin in man.

Ten healthy volunteers each received single and multiple 50-mg doses of indomethacin orally and a single 25-mg dose of [14C]indomethacin intravenously in the absence of and concomitantly with 1200 mg of aspirin as a single dose and in a chronic t.i.d. regimen. Systematic analysis of the data resulted in the isolation and quantification of aspirin's effects on the absorption, distribution, biotransformation, excretion, enterohepatic circulation, and accumulation of indomethacin. The effects of chronic aspirin were to suppress the renal clearance, to increase the biliary clearance, to decrease the efficiency of gastrointestinal absorption, and to enhance the enterohepatic circulation of indomethacin. On concomitant administration of 1200 mg of aspirin t.i.d., mean plasma levels of indomethacin were depressed by 20% after a single oral dose, by a smaller margin after multiple oral doses, and not at all after a single intravenous dose of indomethacin. The mean plasma concentration of orally administered indomethacin was decreased by 8% when given concurrently with a single 1200 mg dose of aspirin. Concomitant chronic therapeutic dosages of indomethacin had no effect on salicylate accumulation from repetitive doses of aspirin.

Adult↗