ABSTRACT
Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.
Subject(s)
Age Factors , Theophylline/metabolism , Adult , Aged , Humans , Male , Middle Aged , Regression AnalysisABSTRACT
Ibopamine (N-methyldopamine O,O'-diisobutyrol ester, hydrochloride) is an ester prodrug of epinine. Epinine is a cardiovascular agent used in congestive heart failure because of its dopaminergic and adrenoreceptor agonist properties. Quantitative analytical methods, using high-performance liquid chromatography coupled with electrochemical detection, were developed for the determination of epinine and its known metabolites in biological media. Epinine was extracted from human plasma and urine via an alumina adsorption procedure; this procedure was also used to estimate epinine conjugates after prior enzymatic hydrolysis. Penicillamine was added to the incubation mixture to inhibit isoquinoline production. Urinary dihydroxyphenylacetic acid levels were obtained using the same alumina adsorption procedure, while a separate analytical procedure utilizing a direct high-performance liquid chromatographic analysis of samples was developed for homovanillic acid and its conjugates. Coefficients of variation for all the assays were below 8%. These methods were used to study the pharmacokinetics and metabolic fate of epinine after oral administration of ibopamine to healthy volunteers.
Subject(s)
Deoxyepinephrine/analogs & derivatives , Deoxyepinephrine/analysis , Dopamine/analogs & derivatives , 3,4-Dihydroxyphenylacetic Acid/urine , Chromatography, High Pressure Liquid , Deoxyepinephrine/blood , Deoxyepinephrine/metabolism , Deoxyepinephrine/urine , Electrochemistry , Homovanillic Acid/urine , Humans , Hydrolysis , MaleABSTRACT
Fenoldopam [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] is a potent renal vasodilator that is currently undergoing Phase II clinical trials. Quantitative analytical methods, based on high-performance liquid chromatography with electrochemical detection (HPLC-ED) after ethyl acetate extraction from plasma or urine were developed for the determination of fenoldopam and its identified metabolites in biological media. The lower limit of quantitation for fenoldopam in plasma was 50 pg/ml. In assays for fenoldopam glucuronide(s) and fenoldopam conjugates, urine was treated with beta-glucuronidase and Glusulase, respectively, and the liberated fenoldopam was quantified by HPLC-ED. A novel assay by dual-electrode (in series) HPLC-ED was developed for the 8-sulfate of fenoldopam. In this method, the 8-sulfate was oxidized to the o-quinone at the first electrode and quantitated at the second electrode after reduction to the catechol. A similar dual-electrode HPLC-ED method was used for 7- and 8-O-methyl fenoldopam. Conjugates of the O-methyl metabolites were determined by HPLC-ED after hydrolysis to O-methyl fenoldopam. These methods have been used to study the kinetics and metabolism of fenoldopam in healthy volunteers. The methods are specific, sensitive, reproducible, and linear over a wide range of concentrations. Precision of the analyses, expressed as coefficients of variation, were less than 10% for all analyses.
Subject(s)
Benzazepines/analysis , Benzazepines/blood , Benzazepines/urine , Biotransformation , Chromatography, High Pressure Liquid/methods , Electrochemistry , Fenoldopam , Humans , Male , Spectrophotometry, UltravioletABSTRACT
SK&F 82526, a benzazepine with a catechol moiety, is a potent, specific renal vasodilator. The method described here for its determination in plasma uses an ethyl acetate extraction and an ether wash, followed by high-performance liquid chromatographic analysis with electrochemical detection. The detection limit is 160 pM. The method was proven accurate, precise and linear over three orders of magnitude (at plasma concentrations ranging from 50 pg/ml to 50 ng/ml). It has been successfully used for plasma determinations of SK&F 82526 in human volunteers following an oral dose of 25-100 mg.
Subject(s)
Benzazepines/blood , Chromatography, High Pressure Liquid/methods , Electrochemistry , Fenoldopam , HumansABSTRACT
A method is described for the extraction of ticrynafen, a new hypotensive agent, and its reduced metabolite from serum and urine. Drug-related material is extracted from biological fluids with ether under strongly acidic conditions and then back-extracted into an alkaline aqueous phase, which is subjected to high-pressure liquid chromatographic analysis. Separations are performed on a reversed-phase column with a mobile phase consisting of phosphate buffer-acetonitrile. This accurate and reproducible method measures serum concentrations of ticrynafen and its reduced metabolite as low as 1.0 and 0.4 microgram/ml, respectively.
Subject(s)
Glycolates/analysis , Ticrynafen/analysis , Animals , Chromatography, High Pressure Liquid , Dogs , Humans , Methods , Ticrynafen/blood , Ticrynafen/urine , Time FactorsABSTRACT
The bioavailability of parenteral cimetidine was tested in 12 volunteers in a balanced three-way crossover study. Blood levels and urinary excretion were compared after intramuscular and intravenous injection and oral administration of 300 mg of cinetidine. The results indicated that the intramuscular and intravenous routes are virtually interchangeable for parenteral cimetidine, and that the oral liquid, although exhibiting a reduced area under the blood level curve as compared with the parenteral doses, nevertheless demonstrated equivalence with respect to the time the blood level remained above 0.5 microgram per ml. The 300-mg cimetidine tablet formulation was found in another group of 12 volunteers to be bioequivalent to a 300-mg dose of oral liquid.
Subject(s)
Cimetidine/metabolism , Guanidines/metabolism , Administration, Oral , Biological Availability , Cimetidine/administration & dosage , Cimetidine/blood , Cimetidine/urine , Humans , Injections, Intramuscular , Injections, IntravenousABSTRACT
A method is described for extraction of cimetidine, a histamine H2-receptor antagonist, from whole blood and urine with subsequent analysis by high-pressure liquid chromatography (HPLC). The drug is extracted from biological fluids with 1-octanol and back-extracted into dilute acid and then into a small volume of ethanol by saturation with potassium carbonate. HPLC analysis is performed on a column of 5-micrometer silica with a mixed mobile phase consisting primarily of acetonitrile. The method measures concentrations of cimetidine as low as 0.05 microgram/ml and is reproducible. Blood levels and urinary excretion data obtained with the analytical procedure are given for a group of human subjects who received 200-mg oral doses of cimetidine.
