Biomedical subjects

J E Axelson

Publications and source records attributed to J E Axelson.

68 records · Page 4Linked to original sources

PubMed1980

Dose-dependent pharmacokinetics of tocainide in the rat.

The pharmacokinetics of tocainide, an experimental antiarrthymic agents, were studied in rats. The concentration of intact drug in plasma and urine samples was determined by an electron capture detector gas chromatographic method. Plasma level and urinary excretion studies revealed the existence of nonlinear kinetics of disposition at and above a 20 mg/kg dose of tocainide. The area under the plasma concentration-time curve increased in a nonlinear fashion with an increase in the dose. Below a 20 mg/kg dose about 19% of the dose was excreted as intact drug in urine while at and above this dose level at least a 100% increase in excretion of intact drug was observed. The extent of inhibition of tocainide metabolism by SKF 525A is more pronounced at a 15 mg/kg dose of tocainide than at 20 mg/kg which suggests that the observed nonlinearity at 20 mg/kg is due to saturation of the metabolism of tocaininde. Study of the effect of route of administration reveals that tocainide is completely absorbed up to a dose of 15 mg/kg, following p.o. or i.p. administration.

Anilides↗

PubMed1980

The effect of phenobarbital and SKF 525A on tocainide pharmacokinetics in the rat.

Studies were carried out to determine the susceptibility of tocainide disposition to the induction and inhibition of drug metabolizing enzymes by using the rat as an animal model. Pretreatment with phenobarbital resulted in a significant reduction in the area under the plasma concentration vs. time curve of tocainide administered i.v. An increase in clearance due to phenobarbital treatment was mainly accounted for by the increase in the disposition rate constant of tocainide. After p.o. or i.v. administration of tocainide, a significant reduction in the percentage of dose excreted as intact drug in the urine was observed in test animals. SKF 525A pretreatment resulted in impairment of the elimination of tocainide as reflected by a reduction in clearance mainly due to a decrease in the disposition rate constant. The inhibition of tocainide metabolism was apparent from the greater than 100% increase in the amount of intact drug excreted in the urine. The differential extent of inhibition of tocainide metabolism observed after a 15 and 20 mg/kg dose supports the involvement of metabolic processes in the nonlinear elimination kinetics of tocainide.

Anilides↗

PubMed1979

Sensitive electron-capture gas-liquid chromatographic assay for the de-ethylated metabolite of metoclopramide.

A procedure is described for determining 4-amino-5-chloro-2-methoxy-N-(2-ethylaminoethyl)benzamide, a metabolite formed by de-ethylation of metochlopramide, in urine from rats. The sampe is extracted (at pH approximately 13) with chloroform and, after treatment with heptafluorobutyric anhydride, derivatives of the extracted compounds are analyzed by gas-liquid chromatography, with electron-capture detection and diazepam as internal standard. The drug and its metabolite are separated, and the latter can be determined in the range 0.4 to 1.85 microgram/ml in the sample. The behaviour of the metabolic during chemical-ionization and electron-impact mass spectrometry is discussed.

Animals↗

PubMed1979

Modification of metoclopramide GLC assay: application to human biological specimens.

A modified electron-capture GLC assay for metoclopramide in human biological specimens is reported. This assay involves the incorporation of a back-extraction method to remove endogenous contaminants. Its applicability was demonstrated by studying the time course of metoclopramide in plasma and urine from a human subject. The lowest quantifiable metoclopramide concentration in plasma was 7 ng/ml, provided 0.5 ml of plasma was used.

Chromatography, Gas↗

PubMed1978

Electron-capture detector GLC technique for estimating tocainide in biological fluids.

A sensitive and specific electron-capture detector GLC method capable of detecting picogram quantities of tocainide, a lidocaine analog, in biological fluids was developed. This method consists of extracting the compound into methylene chloride and derivatizing with heptafluorobutyric anhydride to form the monoheptafluorobutyryl derivative. The derivative formation was confirmed by GLC-mass spectrometry. Quantitative estimation was performed using 1-bromonaphthalene as an internal standard. The minimum detectable level by the electron-capture method was approximately 30 pg/injection as opposed to approximately 3 ng/injection with a flame-ionization detector Linear response was observed in the range from 50 pg to 3 ng using an electron-capture detector. No interference from endogenous substances was observed.

Anilides↗

PubMed1978

Griseofulvin---phenobarbital interaction: a formulation-dependent phenomenon.

The reported interaction of griseofulvin with phenobarbital was studied in the rat following oral administration of different dosage forms. A single oral dose of 15 mg of phenobarbital/kg 24 hr prior to the oral administration of a suspension of 100 mg og griseofulvin/kg in 0.5% polysorbate 80 significantly reduced plasma griseofulvin levels. An increase in the concentration of polysorbate 80 to 2% reduced the extent of the interaction from 50 to 32%. Phenobarbital did not influence plasma griseofulvin levels when griseofulvin was given in either 70% polyethylene glycol 300 (suspensions of 20 or 100 mg/kg) or 100% polyethylene glycol 600 (solution of 50 mg/kg). It is concluded that the observed interaction is formulation dependent and is a result of diminished dissolution and, consequently, reduced absorption of griseofulvin.

Animals↗

PubMed1978

Sensitive electron-capture GLC determination of metoclopramide in biological fluids.

A highly sensitive and specific electron-capture GLC assay capable of detecting picogram quantities of metoclopramide, a procaine derivative, in biological fluids was developed. This assay consisted of extracting metoclopramide from an alkalinized aqueous layer into benzene. A portion of the organic phase was derivatized with heptafluorobutyric anhydride. Quantitative estimation of the derivative was accomplished by adding diazepam, the internal standard, in bezene (750 ng/ml). A calibration curve was prepared for the plasma extracts. Linearity was observed in the range studied (91-825 ng/ml). No interference from endogenous substances was observed. The minimum detectable amount was 1 pg/injection. The structure of the derivative was confirmed by electron-impact and chemical-ionization mass spectrometry. The applicability of this method was shown by a preliminary study of the elimination kinetics of metoclopramide in rats after a 10-mg/kg iv dose.

Animals↗

PubMed1977

Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses.

The subjects were 12 male patients stabilized on methadone for many months or years. A comparison was made of the plasma levels and renal clearance of methadone between patients on "high" doses (80 to 110 mg/day) and those on "low" doses (15 to 40 mg/day). A general trend to higher renal clearance was seen in the "high" -dose group, but on more detailed examination there was a direct correlation only when the patients were categorized by urinary pH. At low pHs, there was nearly a 3-fold increase in renal clearance which was associated with a decreased major metabolite to methadone ratio. No evidence for a difference in rate of metabolism between the two groups was found nor were there differences in hepatic function. It was concluded that urinary pH was a major factor in renal clearance of methadone.

Adult↗

PubMed1977