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O Dale

Publications and source records attributed to O Dale.

50 records · Page 3Linked to original sources
PubMed1986

Binding and distribution of restrictively and non-restrictively eliminated drugs to serum and liver cell cytosol: effects of volatile anaesthetics.

The in vitro binding and distribution of drugs to human serum and rat liver cytosol was examined in a three-compartment distribution dialysis system where the free drug concentration could be determined. The effects of high concentrations of volatile anaesthetics and their metabolites on distribution and binding were also investigated. Restrictively eliminated drugs (warfarin, phenytoin, diazepam) distributed more slowly and demonstrated lower cytosol:serum binding ratios (0.09, 0.11 and 0.11, respectively) as compared with the non-restrictively eliminated drugs propranolol and prazosin with distribution ratios of 0.62 and 1.1, respectively. The rapid distribution in favour of liver cytosol may partly explain the high hepatic extraction ratio of non-restrictively eliminated drugs in vivo. Enflurane showed the most significant influence on drug binding as it was the only compound to displace propranolol and prazosin from serum. Furthermore, enflurane displaced phenytoin and diazepam from both serum and cytosol simultaneously, creating marked increases in the free drug concentrations of 60 and 113%, respectively. Halothane was shown to be a weaker agent than enflurane with respect to the ability to displace drugs from serum proteins and liver cytosol. Neither enflurane nor halothane influenced significantly the binding or distribution of warfarin. In contrast, trifluoroacetic acid did not displace any drugs from cytosol, but displaced restrictively eliminated drugs from serum. It is suggested that the ability of enflurane to displace specific drugs from both serum proteins and liver cytosol may be of clinical relevance.

Adult↗
PubMed1986

Interaction of isoflurane with the binding of drugs to proteins in serum and liver cell cytosol. An in vitro study.

The influence of isoflurane on the binding to human serum and isolated human serum albumin (HSA), of drugs (diazepam, phenytoin and warfarin) highly bound to serum proteins, was studied in vitro by equilibrium dialysis. Distribution dialysis was used to determine the effect of isoflurane on the concomitant binding of the drugs to human serum and rat liver cytosol. Isoflurane (3.3% and 5%) significantly suppressed the binding of diazepam only to HSA by 70 and 81%, respectively. Under clinically relevant experimental conditions, isoflurane increased the free fractions of diazepam and phenytoin by 16 and 11%, respectively. During distribution dialysis 5% of the anaesthetic decreased the binding of both diazepam and phenytoin to human serum by 55%, whereas drug binding to liver cytosol was decreased by 36% for diazepam only. Isoflurane exercised no significant effect on the protein binding of warfarin. It is concluded that any interactions with drug protein binding during isoflurane anaesthesia are unlikely to be of clinical significance.

Animals↗
PubMed1985

Binding of tiaprofenic acid to human sera and isolated serum proteins.

The serum protein binding of tiaprofenic acid (Surgam) has been investigated in vitro by equilibrium dialysis in a physiological buffer of pH 7.40 with a 14C-labelled tiaprofenic acid isotope. The stability of labelled and unlabelled tiaprofenic acid was good during dialysis and an irregular distribution of 6% impurities in the 14C-labelled tiaprofenic acid isotope preparation was corrected for. No differences were found between elderly (74 +/- 4 yrs) and young (32 +/- 6 yrs) individuals, both groups showing a serum protein binding of tiaprofenic acid of 99.0 +/- 0.15%. However, patients with impaired renal function (creatinine clearance 24 +/- 8 ml/min) showed a significantly lower binding of 98.5 +/- 0.35%. Albumin was identified as the main tiaprofenic acid binding protein in human serum with a high affinity binding site characterized by an in vitro dissociation constant, KD, of 3.8 x 10(-6) mol/l and a number of available binding sites, n, of 0.34. Tiaprofenic acid was found not to be displaced from serum protein binding sites by other highly bound drugs. It is concluded that tiaprofenic acid protein binding is characterized by small interindividual variations, but that the decreased binding of tiaprofenic acid in patients with renal failure should be paid some attention to.

Aged↗
PubMed1984

Differences in the serum protein binding of prazosin in man and rat.

The serum protein binding of prazosin in man and rat has been studied in vitro by equilibrium dialysis. Prazosin was more extensively bound in human serum than in rat serum with binding ratios (B/F) of 14.3 +/- 3.4 and 4.4 +/- 0.2 (corresponding to 93.4 and 81.4% bound), respectively. This difference in binding between the species was partly due to qualitative differences between human and rat serum albumin, but also to the lower concentration of albumin in rat serum. Rat serum albumin (RSA) apparently showed two different classes of binding sites for prazosin, one with high (KD = 5.78 X 10(-6) M) and one with low (KD = 1.1 X 10(-4) M) affinity; the former is suggested as representing alpha 1-acid glycoprotein (alpha 1-AGP) with one binding site for prazosin per molecule, the latter as representing RSA with 0.28 binding sites per molecule. Human serum albumin (HSA) and human alpha 1-AGP both showed one class of binding sites with KD values of 2.7 X 10(-5) and 1.95 X 10(-6) M, respectively. HSA possessed 0.5 and human alpha 1-AGP 1 binding site for prazosin per molecule. The binding parameters obtained for the isolated serum proteins overestimated to some degree the total serum protein binding of prazosin in man. This was explained by a specific deviation from the law of mass action. HSA was the major binding protein in human serum at therapeutic concentrations, with ca. 60% of the total binding, the remaining 40% being bound to alpha 1-AGP. Anticipating that the high affinity binding site on the RSA preparation represents the binding of prazosin to alpha 1-AGP, then this protein accounts for 70% of the binding in rat serum, while rat serum albumin accounts for approximately 23%. The binding of prazosin to lipoproteins was insignificant in both species. The observed differences between man and rat in the serum protein binding of prazosin implicate differences in the two species with respect to prazosin pharmacokinetics and the pharmacological effect.

Adult↗
PubMed1984

Glutathione and glutathione S-transferases in rat liver after inhalation of halothane and enflurane.

Male Sprague-Dawley rats were exposed in inhalation chambers to halothane and enflurane in concentrations from 50 ppm-1000 ppm (0.0025-0.05 minimum alveolar concentration; MAC) 6 h a day for 3-9 days. Repeated subanaesthetic concentrations were used to avoid effects of general anaesthesia and to increase the metabolized fraction of the inhaled anaesthetics. Exposure to 0.05 MAC of halothane (500 ppm) and enflurane (1000 ppm) for 9 days reduced the activity of glutathione S-transferases. A decrease in liver concentration of reduced glutathione (GSH) was observed after inhalation of enflurane, probably caused by metabolic release of inorganic fluoride. The results indicate a decreased detoxifying capacity of rat liver under the given conditions. Inhalation of occupational related concentrations of the anaesthetics (50 ppm) did neither affect the activity of the transferases nor the concentration of GSH in rat liver.

Anesthetics↗
PubMed1984

Displacement of some basic drugs from human serum proteins by enflurane, halothane and their major metabolites. An in vitro study.

The influence of volatile anaesthetics (halothane, enflurane) on the serum protein binding of three highly bound basic drugs has been studied in vitro by equilibrium dialysis. Radioactive labelled isotopes were used for the determination of drug concentrations. Enflurane, halothane and the halothane metabolite trifluoroacetic acid (TFA) inhibited the binding of diazepam to serum and to its main binding protein, albumin. The binding of diazepam to albumin was inhibited in a competitive manner and was not related to the anaesthetic potency of the vapours. Thus the observed displacement of diazepam should be regarded as a side-effect of the volatile anaesthetics. The binding of propranolol and prazosin in serum was not significantly influenced by the investigated anaesthetics. At clinically relevant concentrations of the anaesthetics, diazepam was displaced significantly only by enflurane with an increase in free fraction of 60% in serum. TFA in concentrations seen after operation significantly increased the free fraction of diazepam up to 90%. We conclude that enflurane anaesthesia may temporarily potentiate the pharmacological effect of diazepam and that, in the postoperative period following halothane anaesthesia, a more rapid elimination of diazepam could be expected.

Adult↗
PubMed1983

Inhalation of enflurane and halothane at subanesthetic concentrations and effects on circulating serum testosterone, luteinizing hormone and follicle-stimulating hormone in the male rat.

The present study was carried out in order to investigate the effects of inhaled volatile anesthetic gases in subanesthetic concentrations on circulating hormones essential for normal male reproduction. Male mature rats were exposed daily, up to 11 days, to halothane or enflurane in concentrations up to 500 and 1000 ppm, respectively, and thereafter examined for changes in the serum concentration of circulating testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). No significant changes were found for any of the investigated hormones. Based on our results and other reports it is suggested that short-term repeated exposure to halothane and enflurane at subanesthetic concentrations is not associated with any appreciable acute toxicity on male reproductive functions.

Animals↗
PubMed1983

Drug metabolizing enzymes in the rat after inhalation of halothane and enflurane. Different pattern of response in liver, kidney and lung and possible implications for toxicity.

Male Sprague-Dawley rats were exposed in inhalation chambers to halothane and enflurane in concentrations from 50 to 1000 p.p.m. (0.0025 MAC-0.05 MAC) 6 h a day for 3-11 days. No signs of general toxicity were found. There was a normal increase in weight, and normal food consumption, organ to body weight ratios and normal histological findings in liver, kidney and lung. Exposure to 500 p.p.m. (0.05 MAC) of halothane induced the activity of NADPH-cytochrome-c-reductase in the liver, decreased the concentration of cytochrome P-450 in the kidney and decreased all the enzyme concentrations measured in lung microsomes. Exposure to halothane 50 p.p.m. (0.005 MAC) and enflurane produced only minor changes. It is concluded that the inhalation of halothane, in contrast to enflurane, may affect drug metabolism and thereby drug kinetics and toxicity. Halothane may increase its own toxicity by increasing the activity of NADPH-cytochrome-c-reductase in liver. An organ differentiation in enzymatic response was observed.

Animals↗
PubMedDate not supplied

Effects of thiopental on transport and metabolism of glutamate in cultured cerebellar granule neurons.

This study was performed to analyze the effects of the barbiturate thiopental on neuronal glutamate uptake, release and metabolism. Since barbiturates are known to bind to the GABA(A) receptor, some experiments were carried out in the presence of GABA. Cerebellar granule neurons were incubated for 2 h in medium containing 0.25 mM [U-(13)C]glutamate, 3 mM glucose, 50 microM GABA and 0.1 or 1 mM thiopental when indicated. When analyzing cell extracts, it was surprisingly found that in addition to glutamate, aspartate and glutathione, GABA was also labeled. In the medium, label was observed in glutamate, aspartate and lactate. Glutamate exhibited different labeling patterns, indicating metabolism in the tricarboxylic acid cycle, and subsequent release. A net uptake of [U-(13)C]glutamate and unlabeled glucose was seen under all conditions. The amounts of most metabolites synthesized from [U-(13)C]glutamate were unchanged in the presence of GABA with or without 0.1 mM thiopental. In the presence of 1 mM thiopental, regardless of the presence of GABA, decreased amounts of [1,2, 3-(13)C]glutamate and [U-(13)C]aspartate were found in the medium. In the cell extracts increased [U-(13)C]glutamate, [1,2, 3-(13)C]glutamate, labeled glutathione and [U-(13)C]aspartate were observed in the 1 mM thiopental groups. Glutamate efflux and uptake were studied using [(3)H]D-aspartate. While efflux was substantially reduced in the presence of 1 mM thiopental, this barbiturate only marginally inhibited uptake even at 3 mM. These results may suggest that the previously demonstrated neuroprotective action of thiopental could be related to its ability to reduce excessive glutamate outflow. Additionally, thiopental decreased the oxidative metabolism of [U-(13)C]glutamate but at the same time increased the detectable metabolites derived from the TCA cycle. These latter effects were also exerted by GABA.

Animals↗
PubMedDate not supplied

A rapid gas chromatographic method for determination of ethylene glycol in serum and urine.

Intoxications with the antifreeze constituent ethylene glycol (EG) occur infrequently, but may be fatal if not recognized and treated promptly. The aim of the present work was to develop an analytical method for rapid diagnosis of EG poisoning and for monitoring EG removal by hemodialysis. EG was measured by gas chromatography upon direct injection of serum or urine samples (50 microL diluted in 200 microL of distilled water containing 2,3-butanediol as internal standard). A 2-m x 2-mm glass column with Chromosorb 101 (80/100 mesh) separates these glycols within four minutes at 200 degrees C, using nitrogen as the carrier gas. The glycols 1,2- and 1,3-propanediol were separated from EG and the internal standard. Acetone, methanol, and isopropanol did not interfere with the analysis. The limit of quantitation of EG was close to 0.5 mM. Because no derivatization, extraction, or concentration procedures were necessary, EG may be determined quantitatively within 30 min, allowing for monitoring of hemodialysis, which should be performed for 15 h in severe cases. The diagnosis of ethylene glycol intoxication in a late stage may be secured by analysis of urine collected on admission.

Adult↗
PubMedDate not supplied

Pharmacokinetics of trazodone during multiple dosing to psychiatric patients.

Steady-state pharmacokinetics of trazodone were investigated over a period of 4 weeks in seven psychiatric patients after repeated oral administrations of 50, 100, and 150 mg twice daily for one, one, and two consecutive weeks, respectively. Unchanged trazodone was determined by high performance liquid chromatography after a basic extraction. A steady-state level of serum trazodone was achieved for the 50 mg dose within 36 hr, while a new steady state level after increasing the dose to 100 mg and then 150 mg twice daily apparently was achieved at 12 hr. Trazodone showed linear pharmacokinetics within the dosage range investigated. The following main parameters were calculated at steady state for psychiatric patients (mean +/- S.D.): t 1/2 = 7.0 +/- 1.2, V beta/F = 0.50 +/- 0.13 l/kg and Clt/F = 3.2 +/- 0.5 l/hr. These pharmacokinetic parameters did not differ significantly from those earlier reported in healthy subjects after a single dose administration of 100 mg when based on an oral availability of trazodone of 65%.

Absorption↗