Drug binding to apparatus: a factor controlling time to equilibrium in equilibrium dialysis studies.
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Dialysis↗
Biomedical subjects
J J Ashley
Publications and source records attributed to J J Ashley.
Synthesis of a fluorescent derivative of cyclosporin A for high-performance liquid chromatography analysis.
A direct assay method for use in studies of cyclosporin binding must be highly sensitive and selective since it must be capable of measuring the concentrations encountered in the protein-free matrix. The failure of current HPLC methods to achieve the sensitivity required for binding studies may be attributed to the use of UV detection, which relies on the relatively weak end-absorption of cyclosporin A. A method involving fluorescence derivatization was sought with the aim of increasing HPLC assay sensitivity. A method is described for producing a fluorescent derivative of cyclosporin A, a compound which has no functional groups which are easily derivatized. However, intramolecular rearrangement of cyclosporin A to form its structural isomer, isocyclosporin A, exposes a secondary amine which can be reacted with dansyl chloride to produce a fluorescent derivative. This two-step derivatization procedure was used as the basis of an HPLC fluorescence assay. Although this assay is not sufficiently sensitive to measure concentrations encountered in the protein-free matrix during plasma binding studies, the method does point to the possible development of a more sensitive assay using a derivatizing reagent other than dansyl chloride.
Amino Acid Sequence↗
Neurologists' use and interpretation of antiepileptic drug monitoring in the treatment of epilepsy.
Of the 150 local Ordinary Members of the Australian Association of Neurologists (AAN), 118 responded to a questionnaire on the use of AED level measurement in the management of epilepsy. AED level measurement is widely employed, but only phenytoin levels were accepted as being reliable by more than 90% of AAN members. Respondents questioned absolute reliance being placed on any of the other AED levels.
Anticonvulsants↗
Curve-fitting in pharmacokinetics--a comparison between gamma- and biexponential fits.
Seven sets of plasma concentration-time data were fitted to both a conventional biexponential equation and a gamma equation. The values of clearance (CL) and mean residence time (MRT) were calculated from the fitted parameters and compared with the values calculated by the trapezoid rule. Both the biexponential and gamma equations provided adequate fits to the data. The values of CL and MRT calculated from the biexponential fits correlated very closely with the values calculated by the trapezoid rule, but there were large discrepancies between the values calculated from the gamma fits and the trapezoid rule. The biexponential model appears to be less sensitive to scatter in the data.
Heart Failure↗
Pharmacokinetics and plasma-concentration-effect relationships of prenalterol in cardiac failure.
Prenalterol was administered as an intravenous infusion at three incremental rates (60, 120 and 240 nmol/min) to five patients with severe cardiac failure. Haemodynamic, hormonal and metabolic variables were measured at the same time as plasma prenalterol concentrations, and the pharmacokinetics of the drug were studied by following plasma concentrations and urinary excretion during and after the infusion. Concentration-dependent increases in cardiac index, stroke index and stroke work index were observed without increases in arterial pressure, heart rate or myocardial oxygen demand. The reninangiotensin-aldosterone system was stimulated, although the extent of stimulation varied among patients. No strong correlations were found between the logarithm of the plasma prenalterol concentration and effect. Plasma clearance of the drug was lower in cardiac patients than in normal volunteers, but a large decrease in renal clearance was partially balanced by an increase in nonrenal clearance. Over the observed range of concentrations, no deviation from linearity was evident, and plasma concentrations of about 150 nmol/l were effective in improving cardiac function without significant side-effects.
Adrenergic beta-Agonists↗
Chronic intractable pain.
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Anticonvulsants↗
Disposition of betamethasone in parturient women after intramuscular administration.
When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection.
Betamethasone↗
Pharmacokinetics of betamethasone in healthy adults after intravenous administration.
The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.
Adult↗
Disposition of betamethasone in parturient women after intravenous administration.
The pharmacokinetics of betamethasone and its phosphate ester are described in nine women in late pregnancy who each received a bolus intravenous dose of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultra-violet detection using sample handling methods which prevent in vitro hydrolysis of the ester. The plasma clearance of betamethasone phosphate (mean = 980 ml/min) and its apparent distribution volume (mean = 5.61) were both higher than previously found for nonpregnant subjects, but its half-life (mean = 4.6 min) was unchanged. Plasma concentrations of betamethasone reached a peak 5-37 min after dosing with betamethasone phosphate, then declined biexponentially with a mean terminal half-life of 262 min. Plasma clearance in pregnant patients (mean = 287 ml/min) was higher than previously reported for nonpregnant subjects. Evidence from urinary excretion and plasma binding measurements and the previously reported transplacental plasma concentration gradient indicated that the increase in clearance was due to increased metabolism possibly by the placental/fetal unit. Plasma binding of beta-methasone was higher in maternal than fetal plasma; binding to alpha 1-acid glycoprotein was more important than binding to albumin as a determinant of this difference. In pregnant patients the decline of endogenous cortisol concentrations in maternal venous plasma was less marked and slower than in nonpregnant subjects. The data now available allows comparison of pharmacokinetic properties between betamethasone and its stereoisomer dexamethasone with respect to their use in preventing neonatal respiratory distress syndrome.
Adult↗
Leaching of 2-(2-hydroxyethylmercapto) benzothiazole into contents of disposable syringes.
A contaminant was found to leach into the contents of two brands of disposable syringes. It was identified as 2-(2-hydroxyethylmercapto) benzothiazole and is believed to be formed during manufacture of the syringes as a result of a reaction between 2-mercaptobenzothiazole, a rubber vulcanization accelerator, and ethylene oxide, used for sterilization. The contaminant was isolated form the rubber plunger-seal and identified using mass, NMR, and UV spectroscopic methods. The amount of contaminant appearing in the contents of syringes was measured; up to 140 micro g was found under clinically relevant conditions. This finding has important implications with respect to the use of these syringes for drug administration and for the collection of blood for drug analyses.
Adsorption↗
Verapamil kinetics in normal subjects and patients with coronary artery spasm.
Verapamil kinetics after intravenous and single and long-term oral dosing were studied in 12 patients with coronary artery spasm and four normal subjects. The decline in plasma concentration after intravenous doses was described by triexponential decay equation, with a terminal half-life (t1/2) of 5 hr. After a single oral dose the bioavailability was only 24%, probably because of the first-pass metabolism. During long-term oral doses of 80 mg every 6 hr, mean peak and trough concentrations were 255 +/- 90 and 105 +/- 38 ng/ml, and mean time at which peak concentration occurred was 1.2 +/- 0.5 hr. Norverapamil, the major active metabolite of verapamil, cumulated during oral dosing and may account for a small proportion of the overall pharmacologic effect. Mean elimination t1/2 during long-term oral dosing was longer than after a single dose (9.6 and 5.7 hr, P less than 0.05). Also, during long-term dosing the area under the curve was more than double that of a single dose, and the apparent oral clearance fell from 4.2 to 1.8 l/min (P less than 0.01). These changes may partly be explained by reduction in presystemic metabolism during long-term therapy. Kinetic predictions based on single doses will not give reliable estimates for long-term oral dosage. Less frequent dose schedule may be possible for prolonged therapy.
Administration, Oral↗
Leaching of a contaminant into the contents of disposable syringes.
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Animals↗
Simultaneous determination of betamethasone, betamethasone acetate and hydrocortisone in biological fluids using high-performance liquid chromatography.
A sensitive, specific, reproducible and rapid high-performance liquid chromatographic method for the simultaneous quantitation of betamethasone, betamethasone 21-acetate and hydrocortisone in biological fluids is described. Hydrocortisone acetate is used as an internal standard and the samples are extracted with dichloromethane before chromatographing on a reversed-phase system. Detection at two ultraviolet wavelengths (254 nm and 240 nm) was used to assess the specificity of the system, and the sensitivity was found to be greater than 10 ng for all steroids. The speed with which this assay can be performed makes it particularly useful for pharmacokinetic studies, and plasma concentration--time profiles resulting from the administration of betamethasone phosphate and betamethasone acetate are presented.
Betamethasone↗
The placental transfer of betamethasone.
The plasma concentrations of betamethasone in a maternal peripheral vein (mv) and in the umbilical vein (uv) were measured at delivery in eleven patients after the administration of betamethasone phosphate equivalent to 8 mg betamethasone. Betamethasone concentrations were measured in plasma using a specific and sensitive HPLC assay. The time interval between the last dose and delivery ranged from 56 min to 800 min and over this time period the mean plasma concentration ratio Cuv/Cmv was 0.28 +/- 0.04 (SD) and exhibited no time dependence.
Adult↗
Disporition of synthetic glucocorticoids. II. Dexamethasone in parturient women.
The plasma level: time profile for dexamethasone after dexamethasone phosphate 8 mg by intravenous bolus (n = 6) or intramuscular injection (n = 6) to pregnant women near term who were to undergo cesarean section was determined by high-performance liquid chromatography. Although pregnancy did not affect the terminal half-life (mean, 142 min; n = 10), the estimate of total plasma clearance was greater in pregnant (559 ml/min) than in nonpregnant women (243 ml/min). The umbilical/maternal venous plasma level ratios of dexamethasone rose with time from last dose to delivery, toward a plateau value of about 0.45. Plasma binding was not different between blood from pregnant (66.6% bound, n = 11) and nonpregnant women (68.1% bound, n = 6) but was lower in umbilical vein blood (60.8% bound, n = 11). Blood/plasma level ratio was higher in maternal (0.92, n = 7) and umbilical vein blood (1.04, n = 7) than in blood from nonpregnant subjects (0.81, n = 12). We conclude that the fetus is a slowly equilibrating compartment for dexamethasone and that the transplacental dexamethasone concentration gradient as well as the increased total clearance in the mother near parturition are most likely attributable to metabolic clearance by the placenta.
Adult↗
Disposition of synethetic glucocorticoids. I. Pharmacokinetics of dexamethasone in healthy adults.
The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest polyexponential equation that is consistent with the data. The terminal phase half-life t1/2 beta was significantly greater (P less than 0.05) in males (mean 201.5 min) than in females (mean 142.3 min). They prolonged t1/2 beta in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 24.5 ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation between t1/2 beta and Vdss among the 12 adults (r = 0.92, p less than 0.001). There were also significant correlation between Vdss and body weight (r = 0.67, p less than 0.05) and t1/2 beta and body weight (r = 0.80, p less than 0.01). The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t1/2 beta. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.
Adult↗
Oral administration of erythromycin stearate: effect of dosage form on plasma levels.
The clinical effectiveness of three different oral dose forms of erythromycin stearate was assessed by following plasma levels during continued dosage. The assessment was carried out in 12 volunteers who took 250 mg of the drug every six hours in a cross-over design with intravenous administration of erythromycin lactobionate as a reference. While in some patients levels which were obtained after the initial dose were low, plasma levels sufficient to inhibit the majority of bacterial pathogens which cause acute respiratory tract infections were obtained and maintained after the second dose.
Adult↗
Quantitation of dexamethasone in biological fluids using high-performance liquid chromatography.
A sensitive and specific method for the quantitation of dexamethasone in plasma and urine is described. The specificity of the method is obtained using adsoprtion chromatography on a high-performance liquid chromatograph. The dexamethasone is detected with a variable-wavelength UV detector. An internal standard technique is used for quantitation of dexamethasone with a minimum sensitivity of 15 ng. Preliminary results of the application of the method to pharmacokinetic studies of dexamethasone in humans are reported.
Chromatography, High Pressure Liquid↗