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Biomedical subjects

M Rowland

Publications and source records attributed to M Rowland.

At least 163 records · Page 9Linked to original sources
PubMed1988

Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol.

1. An intravenous dose of 14C-propofol (0.47 mg/kg) administered to six male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and less than 2% in faeces. 2. The dose was cleared by metabolism with less than 0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulphate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. 3. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 microgram/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 h post dose. 4. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 1/min.

Adult↗
PubMed1988

A model to account for the variation in cyclosporin binding to plasma lipids in transplant patients.

The usefulness of therapeutic monitoring for cyclosporin in transplant patients is still open to question due to variability of the data. One source of variability, the binding within plasma, was examined in renal transplant patients undergoing cyclosporin therapy. The fraction unbound varied between 0.04 and 0.13. A model based on physiochemical principles, involving concurrent partition of the drug between water, cholesterol, and triglyceride, was used to account for the variation in binding. Simulations using this model indicate that plasma cholesterol is a major factor contributing to the variability in fraction unbound and that the effect of triglyceride is less by a factor of four.

Cholesterol↗
PubMed1988

Cyclosporin: erythrocyte binding and an examination of its use to estimate unbound concentration.

Cyclosporin A (CyA) undergoes saturable binding to erythrocytes. Theoretically, measurement of erythrocyte concentration can be used to estimate the unbound concentration, which in turn may be more closely related to response than total plasma concentration. This possibility for estimating unbound concentration was explored in 139 blood samples taken from renal transplant patients who received CyA therapy. In practice, the method proved to be no better than that obtained by assuming a constant fraction CyA in plasma unbound. In this study, however, both methods were too imprecise to be of practical value. If unbound CyA concentration is to be determined it must be measured directly or must be estimated by multiplying total plasma concentration by fraction of drug unbound.

Cyclosporins↗
PubMed1987

Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man.

Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.

Adult↗
PubMed1987

Validation of assay methodology used in pharmacokinetic studies.

Statistical methods for validating assays used in pharmacokinetic studies are discussed. Methods for assessing linearity, variability, and sensitivity are derived. It is proposed that a calibration experiment, in which samples are replicated at three different concentrations, will provide the necessary information to validate an assay prior to commencement of a pharmacokinetic study and during its routine use. A two-stage weighted least squares regression is used to analyze the calibration data. High performance liquid chromatography calibration data are used to illustrate the principles and techniques involved.

Chromatography, High Pressure Liquid↗
PubMed1987

Enoxacin-warfarin interaction: pharmacokinetic and stereochemical aspects.

The interaction between the new quinoline-azaquinoline antibiotic enoxacin and the oral anticoagulant warfarin was investigated in six healthy male volunteers. Enoxacin was found not to affect the hypoprothrombinemic response produced by warfarin but did produce a decrease in the clearance of the less pharmacologically potent enantiomer of warfarin, (R)-warfarin. The decreased clearance of (R)-warfarin produced by concomitant enoxacin administration was found to be a consequence of inhibition by enoxacin of the (R)-6-hydroxywarfarin metabolic pathway.

Adult↗
PubMed1987

Pharmacokinetics of imipenem and cilastatin after their simultaneous administration to the elderly.

The pharmacokinetics of imipenem and cilastatin were studied in a group of six healthy elderly male volunteers following the combined intravenous administration of 500 mg imipenem and 500 mg cilastatin sodium as either single or multiple (6 hourly for 6 days) 20 min constant-rate infusions. The pharmacokinetics of both imipenem and cilastatin in the elderly were similar to those of young individuals with mild renal failure (Verpooten et al., 1984). There was no change in the pharmacokinetics of either species with time following multiple-dosing. Correlations existed between total clearance and the glomerular filtration-rate (51Cr-EDTA) for both imipenem and cilastatin.

Aged↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗
PubMed1987

Cyclosporin-phenytoin interaction: re-evaluation using metabolite data.

1 Freeman et al. (1984) evoked enzyme induction to explain the lower plasma concentration of cyclosporin following phenytoin co-administration in man. 2 We have examined the whole blood concentration data of two metabolites of cyclosporin, as well as unchanged drug, all measured by h.p.l.c., associated with the above mentioned study. 3 Phenytoin produced no significant effect on either the terminal half-life of both metabolites or the ratio of area under the concentration-time curve of metabolite to parent drug. 4 These data strongly suggest that phenytoin reduces the absorption of cyclosporin; they do not generally support the idea that phenytoin induces cyclosporin metabolism.

Biological Availability↗
PubMed1987

Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.

1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance.

Adult↗
PubMed1987

Inter-relationship among individual vitamin K-dependent clotting factors at different levels of anticoagulation.

1. The effect of subtherapeutic doses of warfarin on the activities of the four vitamin K-dependent clotting factors was studied at steady state in five patients each of whom had completed a therapeutic course of anticoagulation. 2. The four clotting factor activities were shown to be depressed to a similar extent for a given dose of warfarin. 3. The prothrombin complex activity was significantly lower than that of any of the clotting factors.

Aged↗
PubMed1987

Cyclosporin: measurement of fraction unbound in plasma.

A reproducible ultracentrifugation method has been developed for the measurement of the fraction of cyclosporin (CyA) unbound in plasma. The sample is centrifuged to remove any particulate matter, ultracentrifuged in polyallomer tubes and then frozen in liquid nitrogen. Appropriate sections are then cut from the tube for determination of the concentration of radioactivity and calculation of fraction drug unbound. Using this method, the fraction unbound has been measured in plasma from renal transplant patients receiving CyA and found to range between 0.04 to 0.122. The binding is temperature-dependent and principally hydrophobic.

Cyclosporins↗
PubMed1986

A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations.

A dispersion model of hepatic elimination, based on the residence time distribution of blood elements within the liver, is presented. The general rate equations appropriate for describing the hepatic output concentration of a tracer solute are derived. Particular consideration is given to events following a bolus input dose of a tracer. The model is shown to be compatible with the known hepatic architecture and hepatic physiology. The model has been fitted to hepatic outflow data for red blood cells, albumin, and other noneliminated solutes. The experimental data suggest a high degree of dispersion of blood elements within the liver. The model has also been used to evaluate the effects of changes in enzyme activity, hepatic cell permeability, blood flow, and protein binding on the outflow concentration vs. time profiles of solutes.

Animals↗
PubMed1986

A dispersion model of hepatic elimination: 2. Steady-state considerations--influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity.

The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the "well-stirred" model (complete mixing of blood elements) and the "parallel-tube" model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.

Administration, Oral↗
PubMed1986

A dispersion model of hepatic elimination: 3. Application to metabolite formation and elimination kinetics.

A dispersion model of hepatic elimination is presented to describe metabolite formation and elimination kinetics within the liver, consistent with the known physiology and biochemistry of this organ. The model is based on the spread in residence times of blood flowing through the liver. This dispersion model is shown to be more consistent with transient and steady-state data obtained after the single passage of phenacetin and acetaminophen through the liver (both normal and retrograde perfusions) than other models of hepatic elimination. The dispersion model is suitable for the evaluation of enzyme heterogeneity using experimentally obtained metabolite data.

Acetaminophen↗