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Biomedical subjects

J E Axelson

Publications and source records attributed to J E Axelson.

At least 55 records · Page 3Linked to original sources
PubMed1986

Placental transfer of diphenhydramine in chronically instrumented pregnant sheep.

To study the placental transfer and pharmacokinetics of the H1 receptor blocker, diphenhydramine [2-(diphenylmethoxy)-N,N-dimethylethylamine], 100 mg of the drug was administered to four pregnant sheep (122-129 d gestation) by intravenous injection through catheters chronically implanted in the ewe and fetus. Rapid placental transfer occurred, with peak fetal plasma concentrations occurring within 5 min after injection. The fetal-maternal ratio of the area under the plasma concentration versus time curves averaged 0.85, indicating significant fetal exposure to the drug. The average apparent terminal elimination half-life in the ewe (52 min) was not significantly different from that obtained in the fetus (46 min). The maternal total body clearance was 3.6 L X h-1 X kg-1, and the volume of distribution at steady state was 3.2 L/kg. In summary, this study demonstrates rapid and extensive placental transfer of diphenhydramine after maternal drug administration. Since placental permeability to lipid-soluble compounds does not differ greatly in different species, it is likely that a similar situation exists in humans.

Animals↗
PubMed1986

Effect of pH-adjustment of bupivacaine on onset and duration of epidural analgesia in parturients.

Previous studies have reported that elevation of the pH of local anaesthetics is associated with enhanced quality and duration of block. This study investigated the effect, on time to onset and duration of analgesia, of pH adjustment of 0.25 per cent bupivacaine immediately prior to injection into the epidural space in parturients. Addition of 0.1 ml of 8.4 per cent sodium bicarbonate to 20 ml of 0.25 per cent bupivacaine consistently raised the pH of the local anaesthetic from 5.65 to 7.26 (mean values). Thirty parturients received an epidural injection of 8 ml of pH-adjusted 0.25 per cent bupivacaine and a control group of 30 parturients received 8 ml of the standard commercial preparation of 0.25 per cent bupivacaine. Elevation of the pH of the local anaesthetic significantly increased the speed of onset of analgesia from 6.0 minutes to 3.2 minutes and the duration of analgesia was significantly lengthened from 79.4 minutes to 96.5 minutes. There was no significant influence on time to peak effect, nor on mean maternal plasma levels of bupivacaine.

Adult↗
PubMed1985

Applicability of capillary gas liquid chromatography to the measurement of free fraction of disopyramide in human plasma.

A sensitive and specific capillary gas liquid chromatographic nitrogen/phosphorus selective detection technique was used to measure unbound disopyramide in human plasma. The concentration dependent protein binding of disopyramide was examined. Various concentrations of disopyramide alone ranging from 0.5 to 10.0 micrograms/ml in 0.4 ml of isotonic phosphate buffer (pH 7.4) were dialyzed for 6 hours at 37 degrees C, against 0.4 ml blank plasma from five healthy volunteers. The concentration-dependent binding of disopyramide was confirmed. The average free fraction for disopyramide at concentrations of 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 and 10.0 micrograms/ml were 0.14, 0.15, 0.20, 0.27, 0.30, 0.34 and 0.53, respectively.

Chromatography, Gas↗
PubMed1984

Simultaneous quantitation of disopyramide and its mono-dealkylated metabolite in human plasma by fused-silica capillary gas chromatography using nitrogen-phosphorus specific detection.

A nitrogen-specific detector gas-liquid chromatographic assay method is reported which provides improved selectivity and sensitivity for disopyramide and its mono-N-dealkylated metabolite using a crosslinked fused-silica capillary column. The quantitation of disopyramide and mono-N-dealkylated disopyramide was accomplished by injecting trifluoroacetic anhydride-treated samples containing derivatized internal standard p- chlorodisopyramide , into a gas chromatograph equipped with a nitrogen--phosphorus detector and an automatic liquid sampler. A 25 m X 0.31 mm crosslinked, 5% phenylmethyl silicone-coated fused-silica column was utilized and samples were injected using the splitless injection mode. Linearity was observed in the range 0.05-5.00 micrograms/ml for disopyramide and 0.02-3.00 micrograms/ml for the mono-N-dealkylated metabolite. The coefficient of variation was found to be within 10% for both compounds in the concentration range studied.

Chromatography, Gas↗
PubMed1984

Nonlinear bioavailability of metoclopramide in the rat: evidence for saturable first-pass metabolism.

In vivo and in vitro experiments were conducted in rats to examine the possibility of either extrahepatic metabolism or saturable first-pass effect as an explanation for the unusual presystemic clearance of metoclopramide (I) previously reported. In vivo studies involved two-thirds hepatectomized rats and animals pretreated with carbon tetrachloride to induce hepatic necrosis, whereas in vitro studies involved incubation of equal amounts of I (5.0 mumol/mL) with various tissue homogenates (viz., liver, kidney, and lung) or their 9000 X g supernatant fractions. Results suggest that the metabolism of I principally occurs in the rat liver, and there was no evidence suggesting the involvement of kidney or lung tissue in the metabolism of I. Forty-eight-hour cumulative urinary excretion studies following oral and intravenous administration of less than or equal to 5.0 mg/kg of metoclopramide hydrochloride were conducted. The bioavailability (F) values of I at dosage levels 0.1, 0.5, 1.0, and 5.0 mg/kg were 0.49, 0.75, 0.77, and 0.83, respectively. It is concluded that the liver is the primary organ for the metabolism of I in the rat and that the drug exhibits dose-dependent hepatic first-pass metabolism.

Animals↗
PubMed1984

Factors affecting quinidine protein binding in humans.

The free (unbound) concentration of drug in plasma is often an important determinant of pharmacological and toxicological effects. Unfortunately, studies examining the factors influencing the free fraction of quinidine in plasma have yielded inconsistent results. It is probable that differences in the type of blood collection tubes utilized and the analytical procedure employed biased some of these estimates of quinidine binding. The present study was executed in a manner free of factors now known to introduce artifacts into estimates of the free fraction of quinidine. In healthy volunteers, the free fraction of quinidine (1.0 microgram/mL) was 0.129 +/- 0.019 (mean +/- SD) and was constant throughout the therapeutic range. A high-affinity, low-capacity binding site (K = 1.17 X 10(5) M-1; nP = 3.49 X 10(-5) M) and a low-affinity, high-capacity binding site (K = 1.33 X 10(3) M-1; nP = 3.14 X 10(-3) M) were identified. The characteristics of quinidine binding in a 4.5-g/dL solution of human serum albumin (K = 3.05 X 10(3) M-1; nP = 1.36 X 10(-3) M) suggested that the low-affinity, high-capacity binding site was on this quinidine free fraction increased from 0.114 to 0.231. A lidocaine concentration of 250 micrograms/mL caused a similar increase. Patients suffering traumatic injury had a significant increase in alpha 1-acid glycoprotein concentration (197 mg/dL) and a decreased quinidine free fraction (0.075 +/- 0.019). Patients with hyperlipidemia had free fractions similar to those observed in healthy individuals (0.118 +/- 0.019).(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1984

Stereospecific salivary excretion of tocainide enantiomers in man.

Saliva and plasma samples collected from four healthy volunteers who had received racemic tocainide by intravenous infusion for 20 minutes were analysed by a stereospecific and sensitive gas chromatographic method. The enantiomeric composition of mixed saliva obtained for a period of 48 hrs have been determined and compared with the corresponding plasma profiles. The concentration of each enantiomer in saliva tended to be greater than those in the corresponding plasma sample, such that the mean saliva to plasma ratio for S(+) tocainide was 2.07 +/- 0.50 (SEM) and for the R(-) isomer 3.683 +/- 0.76 (SEM). Marked intersubject variability was found in the saliva/plasma ratio of both isomers, however, the correlation of saliva/plasma concentrations in each volunteer was good and ranged from r = 0.910 to 0.987 for S(+) tocainide and r = 0.884 to 0.986 for R(-) tocainide. There was a 6-fold difference between saliva and plasma concentration of R(-) isomer in one subject whose saliva pH ranged from 6.9 to 7.1. The difference was only 3.5 fold in another subject whose saliva pH was consistently higher (7.4 to 7.5). Therefore, the saliva/plasma ratio appeared to depend on pH, increasing with decreasing pH. However, the correlation between the saliva/plasma ratio observed and the ratio predicted was poor. Mechanisms other than passive diffusion are likely to be involved in the transfer of tocainide enantiomers from plasma to saliva and are more pronounced with the levo isomer.

Adult↗
PubMed1983

Electron-capture determination of metoclopramide in biological fluids using fused silica capillary columns. Application to placental transport studies in sheep and humans.

An electron-capture gas-liquid chromatographic assay for metoclopramide using cross-linked fused silica capillary columns which provides improved selectivity and sensitivity is reported. A 25 m X 0.31 mm fused silica capillary column was used for all analyses. Linearity was observed in the range of 4--40 ng of metoclopramide base per 0.25--0.5 ml of plasma. This represents from ca. 0.9--9.0 pg at the detector employing a split ratio of 30:1 and an injection volume of 2 microliters. Applicability of the method is demonstrated by the analysis of human and sheep plasma (maternal, fetal and neonatal) from metoclopramide placental transfer studies.

Adult↗
PubMed1983

Placental transport of metoclopramide: assessment of maternal and neonatal effects.

Twenty-three patients undergoing general anaesthesia for Caesarian section for healthy term pregnancies were entered into a double blind study using metoclopramide (MCP) and a normal saline placebo. Of these patients, eight received intravenous metoclopramide, 12 a normal saline placebo and three were lost to clinical follow-up. The maternal gastric volumes were measured and maternal and foetal MCP plasma concentrations were determined by gas-liquid chromatography. The Neurological and Adaptive Capacity Score tests of Amiel, Barrier and Schnider (NACS) were used to attempt evaluation of neonatal responses to MCP. Maternal gastric volume was significantly lower (p less than 0.05) in the treated patients. There were no marked differences in Apgar scores, cardiovascular parameters or neurobehavioural scores between the treated and untreated groups of neonates. At no time were the foetal metoclopramide plasma concentrations observed to exceed maternal values.

Adult↗
PubMed1982

Electron-capture gas-liquid chromatographic determination of tocainide in biological fluids using fused silica capillary columns.

Gas-liquid chromatography using capillary columns and electron-capture detection has been employed for the determination of a new antiarrhythmic drug, tocainide, in rat plasma and urine. The drug is extracted from a basified solution along with an internal standard, monoethylglycine xylidide, and subsequently reacted with heptafluorobutyric anhydride. The 50 m x 0.2 mm fused silica capillary column was coated in the laboratory with Carbowax 20M. Linearity of detector response was established in the range of 50-1000 ng of tocainide hydrochloride per 100 microliter of plasma or urine. This represented 14-270 pg of the free base at the detector, using a split ratio of 1:25 and an injection volume of 2 microliter. The derivatization method and chromatographic assay are well suited for monitoring of plasma or urine samples. The applicability of the method is demonstrated by the analysis of rat plasma collected over a period of 7 h after intravenous administration of 20 mg/kg of tocainide hydrochloride.

Animals↗
PubMed1982

Metabolism of tocainide in the rat.

The metabolism of tocainide, an oral antiarrhythmic agent, was studied in male Wistar rats following oral administration of 15 mg/kg of tocainide hydrochloride. Qualitative and quantitative identification of the metabolites in urine was carried out by GC-mass spectrometry and electron capture detector gas chromatography. About 15-20% of the dose administered was excreted as intact drug in the urine. An additional 20% of the dose was present as acid hydrolysable conjugates. Enzymatic hydrolysis (beta-glucuronidase) revealed half of the acid hydrolysable conjugates to be a glucuronide. The enzyme mediated hydrolysis was blocked by its specific inhibitor saccharo-1,4-lactone. N-acetyl tocainide, an oxidatively deaminated tocainide, an aldehyde adduct of tocainide, and a cyclic hydantoin derivative of tocainide were also identified as metabolites in the urine samples.

Animals↗
PubMed1982

Species differences in the urinary excretion of the novel primary amine conjugate: tocainide carbamoyl O-beta-D-glucuronide.

The metabolism of the antiarrhythmic drug tocainide (I) has been shown previously to occur via a novel pathway involving the addition of carbon dioxide to the primary amine nitrogen of I followed by conjugation with glucuronic acid. The product of this reaction, tocainide carbamoyl O-beta-D-glucuronide (II), the principal metabolite of I in humans, has been found to cyclize under strongly basic conditions to form 3-(2,6-xylyl)-5-methylhydantoin (III). Thus, evidence for the existence of II can be obtained by two different procedures: conversion of II to III in the presence of strong base and by hydrolysis of II with beta-glucuronidase. The principal purpose of the present investigation was to identify suitable species for studies of the mechanism involved in the formation of II, as well as to find an animal model suitable for toxicological evaluation of tocainide and structurally related compounds. Eight animal species were examined to identify those capable of metabolizing I into II. The fraction of an intraperitoneal dose excreted in urine as II was estimated by measurement of tocainide released by beta-glucuronidase mediated hydrolysis of urine and by the quantitation of III formed after alkalinization of urine samples. Urinary recovery of unchanged drug ranged from 9.5% of the dose in the gerbil to 48.7% in the cat. The percent of the dose excreted in urine as acid hydrolyzable conjugates ranged from less than 1% in the gerbil to a mean of 13% in the rabbit. Guinea pigs, dogs, cats, rabbits, and pigtail monkeys excreted amounts of II ranging from 0.2 to 2.4% of the dose. Thus, none of the species appeared to be a suitable model for the study of the mechanism of formation of II because of the quantitative insignificance of this pathway.

Animals↗
PubMed1981

3-(2,6-Xylyl)-5-methylhydantoin--a metabolite or a metabonate of tocainide in rats.

1. G.1.c.-mass spectrometric analysis of urine extracts from rats dosed with tocainide (I) revealed the presence of cyclic compound identified as 3-(2,6-xylyl)-5-methylhydantoin (IV) derived from tocainide. 2. Evidence indicates that IV is derived from a conjugate of tocainide (tocainide carbonyl O-beta-D-glucuronide) (III) in humans. 3. Results of the present study indicate that in addition to being formed from a conjugate, IV is generated directly from tocainide in vivo in rats. Possible mechanisms for the formation of IV in rats in vivo are discussed.

Animals↗
PubMed1980

Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Adult↗