Variable Plasma Concentrations Research Articles

Plasma and Skin Concentration of 5-Methoxypsoralen in Psoriatic Patients After Oral Administration

The aim of this work was to investigate the distribution of 5-methoxypsoralen in the skin after oral administration of the drug and to examine the correlation between skin and plasma concentrations. 5-Methoxypsoralen skin concentration was measured in both healthy and psoriatic sites of 10 psoriatic patients after single and multiple oral doses. The results obtained show that 5-methoxypsoralen accumulates at higher levels in the more external layers of the skin after oral administration. The high affinity of drug for the stratum corneum was confirmed by in vitro skin affinity measurements. The concentration of 5-methoxypsoralen in the skin was similar in both psoriatic and healthy sites, indicating that the pathology does not influence drug distribution in the skin. After single dose administration, a linear correlation was found between skin and plasma drug concentration. After multiple dose administration, drug concentration in the skin was fairly constant despite the variable plasma concentrations in different subjects.

Plasma cytokine parameters and mortality in patients with chronic heart failure.

Inflammatory immune activation is an important feature in chronic heart failure (CHF). Little is known about the prognostic importance of tumor necrosis factor-alpha (TNF-alpha), soluble TNF-receptor 1 and 2 (sTNF-R1/sTNF-R2), interleukin-6 (IL-6), and soluble CD14 receptors (sCD14) in CHF patients. In 152 CHF patients (age 61+/-1 years, New York Heart Association [NYHA] class 2.6+/-0.1, peak VO(2) 17.3+/-0.6 mL. kg(-1). min(-1), mean+/-SEM) plasma concentrations of immune variables were prospectively assessed. During a mean follow-up of 34 months (>12 months in all patients), 62 patients (41%) died. Cumulative mortality was 28% at 24 months. In univariate analyses, increased total and trimeric TNF-alpha, sTNF-R1, and sTNF-R2 (all P</=0.0001), sCD14 (P=0.0007), and IL-6 (P=0.005) predicted 24-month mortality. With multivariate analysis and receiver operating characteristics, sTNF-R1 emerged among all cytokine parameters as the strongest and most accurate prognosticator in this CHF population, regardless of follow-up duration and independently of NYHA class, peak VO(2), VE/VCO(2) slope, left ventricular ejection fraction, and wasting (P<0.001). The receiver operating characteristic area under the curve for sTNF-R1 was greater than for sTNF-R2 at 6, 12, and 18 months (all P<0.05). sTNF-R1 was the strongest and most accurate prognosticator, independent of established markers of CHF severity. Assessment of sTNF-R1 may be useful in identifying patients who are at high risk of death and in monitoring patients undergoing anti-TNF-alpha treatment.

Pharmacokinetics of fentanyl after intravenous and transdermal administration in goats

Abstract Objective To evaluate disposition of fentanyl in goats after IV and transdermal administration. Animals 8 healthy 2-year-old goats weighing 31.8 to 53.6 kg (mean ± SD, 40.4 ± 7.5 kg). Procedure Each goat was given 2 treatments consisting of fentanyl administered IV (2.5 μg/kg of body weight) and via a transdermal patch (50 μg/h). There was a 2-month interval between treatments. Blood samples were collected at specified times and analyzed in duplicate to determine plasma fentanyl concentrations. Pharmacokinetic values were calculated, using a computerized modeling program. Results Administration of fentanyl was tolerated by all goats. Intravenous administration of fentanyl resulted in a transitory increase in rectal temperature that was not clinically important. Terminal elimination half-life after IV administration was 1.20 ± 0.78 h, volume of distribution at steady state was 1.51 ± 0.39 L/kg, and systemic clearance was 2.09 ± 0.62 L/kg/h. Transdermal administration of fentanyl resulted in variable plasma concentrations, with peak plasma concentrations ranging from 1.12 to 16.69 ng/ml (mean ± SD, 6.99 ± 6.03 ng/ml) and time to peak concentration ranging from 8 to 18 hours (mean ± SD, 13 ± 4.5 hours). After removal of the transdermal patch, mean ± SD terminal elimination half-life was 5.34 ± 5.34 hours. Conclusions and Clinical Relevance Intravenous administration of fentanyl (2.5 μg/kg) in goats results in a relatively short half-life that will limit its use for management of pain. Transdermal administration of fentanyl (50 μg/h) in goats results in variable plasma concentrations that may exceed those anticipated on the basis of a theoretical delivery rate, but stable plasma concentrations of fentanyl may not be achieved. (Am J Vet Res 1999;60:986–991)

Application of the area under the curve of carboplatin in predicting toxicity and efficacy

Current cytotoxic chemotherapy dosing is largely empirical and guided by the concept of improved therapeutic outcome with greater total dose delivered over a fixed period of time, i.e., dose intensity (1,2). Consequently, chemotherapy is clinical1 given as the maximum dose tolerated by the patient (3). In contrast to antibiotics, the intrinsic sensitivity of tumour or host cells to a cytotoxic drug is unclear, such that the likelihood of response or toxicity is not usually predictable prior to treatment. Additionally, most cytotoxic agents have a narrow therapeutic index but no clear surrogate markers to monitor for efficacy or toxicity Since the pharmacokinetics of chemotherapy drugs is highly variable between patients, one attempt in overcoming this problem is the traditional dosing in milligrams per square metre (mg/m2) of body surface area (BSA) (4). This BSA-based dosing is derived from the fact that the lethal dose in 10% of the population (LD,,) in animals is better correlated to the maximum tolerated dose (MTD) in humans when expressed in mg/m2 than in mg/kg (5). Nevertheless, inherent interpatient variability means that standardized dosing in mg/m2 can still lead to variable plasma concentrations (6). As a result, patients may be exposed to too much or too little drug, leading to potential toxicity or therapeutic failure. Moreover, since the MTD is established clinically on the dose producing significant toxicity in 50% of patients, extrapolating this dosing to all patients may lead to underdosing in half of the patients. The total area under the concentration-time curve (AUC) for a particular drug is the product

Dose-related haemodynamic effects and pharmacokinetics of oral nicorandil in patients evaluated for chest pain

We studied the acute haemodynamic dose response of nicorandil, a combined nitrate and potassium channel opener, in patients evaluated for chest pain. Single dose oral nicorandil (5, 10, 20, or 30 mg) or placebo was given to 42 right-heart catheterized patients using a randomized block design. Persistent, significant ( P < 0.05) haemodynamic changes occurred primarily after 30 mg. Arterial systolic pressure fell significantly after all doses and remained reduced (maximum, 31 mmHg) up to 6 h after 30 mg; heart rate increased significantly up to 1 h. Individual haemodynamic sensitivity varied and three patients (1, 10 mg; 2, 30 mg) developed transient symptomatic hypotension associated with bradycardia. Pulmonary artery systolic pressure (diastolic was unchanged) declined significantly (maximum, 5 mmHg) up to 6 h after 30 mg whereas pulmonary capillary wedge (baseline normal) and mean right atrial pressures decreased transiently. Cardiac index (baseline normal) declined slightly (significantly after 30 mg); however, stroke volume index and stroke work index were significantly and persistently reduced after all doses. Total systemic vascular resistance declined slightly after 30 mg. Individual plasma nicorandil concentrations were variable and systemic bioavailability was reduced compared with values reported in healthy subjects. Nicorandil demonstrated cardiac unloading actions. Variable plasma concentrations, haemodynamic effects, and patient sensitivity warrant low initial doses with individual dose titration, especially if cardiac filling pressures are low.

Neuropathic Pain in a Cancer Patient Responding to Subcutaneously Administered Lignocaine

To demonstrate difficulties encountered in alleviating neuropathic pain in a terminally ill cancer patient, with the very tentative diagnosis of postherpetic neuralgia. A multidisciplinary pain department in a university hospital. A patient with Hodgkin's lymphoma and leiomyosarcoma in the liver developed an unusual manifestation of neuropathic pain. Oral drug treatment with morphine associated with amitriptyline, valproic acid, mexilitine, flufenazine, and methylprednisolone failed to suppress pain attacks. Only the subcutaneous instillation of lidocaine (2 mg/kg/h) could partially suppress pain. A dorsal root entry zone lesion intervention could only temporary stop the pain attacks. Infiltration and nervous stimulation techniques were not helpful. In determining pain control, the visual analog scale rating scale and the number of attacks per hour were considered. Only the subcutaneous administration of lignocaine could partially suppress pain. Because of the patient's poor hepatic circulation, variable lidocaine plasma concentrations were responsible for intolerable side effects. Subcutaneous lignocaine administration remains a useful method in treating neuropathic cancer pain. The poor metabolic condition of the patient can lead to deleterious high plasma levels. A dorsal root entry zone lesion could only temporarily stop the pain.

Rapid increase in plasma endothelin concentrations during percutaneous balloon dilatation of the mitral valve in patients with mitral stenosis.

To investigate the relation between plasma concentrations of immunoreactive endothelin and haemodynamic variables before and after percutaneous transvenous balloon dilatation of the mitral valve. Prospective study. National cardiovascular centre. 25 patients with mitral stenosis and 26 healthy volunteers. Plasma concentrations of immunoreactive endothelin were measured in the pulmonary artery, left atrium, ascending aorta, and femoral vein before and after balloon dilatation of the mitral valve. Peripheral venous concentrations (mean (SD)) of endothelin were higher in the patients with mitral stenosis than in the healthy volunteers (1.76 (0.51) v 1.37 (0.45) pg/ml, p < 0.05) and they correlated with the mean left atrial pressure (r = 0.74, p < 0.01). Balloon dilatation of the mitral valve reduced the mean left atrial pressure without changing the mean right atrial pressure, systemic arterial pressure, heart rate, or cardiac index. Concentrations of plasma endothelin in the femoral vein increased from 1.76 (0.51) to 3.39 (2.46) (p < 0.01), 4.82 (2.34) (p < 0.001), and 2.43 (0.52) pg/ml (p < 0.05) at 15 and 30 minutes and 24 hours after the procedure. The concentration of endothelin in the pulmonary artery also increased from 1.85 (0.85) to 4.32 (1.58) pg/ml (p < 0.01) 30 minutes after the dilatation, whereas there were no appreciable changes in endothelin concentration in the left atrium or ascending aorta. Plasma endothelin concentrations were higher in patients with mitral stenosis than in healthy volunteers and the increase was proportional to left atrial pressure. After balloon dilatation of the mitral valve there was an abrupt rise in endothelin in the femoral vein and pulmonary artery but no change in left atrial or aortic blood samples. These findings suggest that endothelin may be another vasoactive substance involved in congestive heart failure.

Production of transgenic sheep with growth‐regulating genes

Pronuclei of fertilized sheep ova were injected with fusion genes consisting of the mouse metallothionein-I promotor/regulator ligated to either the structural gene for bovine growth hormone (mMTbGH) or to a minigene for human growth hormone-releasing factor (mMThGRF). From a total of 842 sheep ova injected with mMTbGH and transferred into recipient ewes, 47 lambs were born. Two of the lambs were transgenic with mMTbGH, and both had bGH mRNA present in liver, kidney, and gut. In one lamb, plasma growth hormone was as high as 700 ng/ml. From a total of 435 sheep ova injected with mMThGRF and transferred to recipients, 54 lambs were born and 9 fetuses were collected. Nine of the 63 had integrated the mMThGRF gene. One of the nine had high concentrations of immunoassayable hGRF in its plasma and high variable plasma concentrations of ovine growth hormone. The lamb that expressed the hGRF gene did not release GH in response to an hGRF challenge. Four of five fetal offspring of a nonexpressing mMThGRF transgenic ram also contained the mMThGRF gene and, like the sire, failed to express the gene as determined by either liver hGRF mRNA or by plasma hGRF. Growth of the single transgenic lamb expressing hGRF was similar to control lambs. These studies demonstrate efficient introduction of genes into the sheep genome and indicate that transgenes are expressed and heritable.

Clinical pharmacokinetics of beta-adrenoceptor antagonists. An update.

The beta-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug. Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma beta-adrenoceptor antagonist concentration measurement is usually unnecessary. The investigation of the clinical pharmacokinetics of the beta-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

Plasmolysis, Red Blood Cell Partitioning, and Plasma Protein Binding of Etofibrate, Clofibrate, and Their Degradation Products

Etofibrate (I), the ethylene glycol diester of clofibric and nicotinic acids, degrades almost equally through both half-esters with half-lives of ~10 and 1min in fresh dog and human plasma, respectively. The nicotinate V degrades with half-lives of ~12hr and 50min in fresh dog and human plasma, respectively. Ester III and clofibrate VI degrade by saturable Michaelis–Menten kinetics in fresh human plasma, with similar maximum initial rates and respective terminal first-order halflives of 12 and 26min. Tetraethyl pyrophosphate at 100 μg/ml inhibited human plasma and red blood cell esterases permitting plasma protein binding and red blood cell partitioning studies. The red blood cell-plasma water partition coefficient was 5.4 for 0.2-80 μg/ml of I. Clofibrate (VI) showed a saturable erythrocyte partitioning that decreased from 7.8 (10 μg/ml) to 1 (50 μg/ml). The strong binding of I and VI to ultrafiltration membranes necessitated the determination of their plasma protein binding by the method of variable plasma concentrations of erythrocyte suspensions to give 96.6% (0.2-80 μg/ml) and 98.2% (13.6-108.4 μg/ml) binding, respectively. Methods for the determination of the parameters of saturable and nonsaturable plasma protein binding for unstable and membrane-binding drugs by the method of variable plasma concentrations in partitioning erythrocyte suspensions are presented.

The pharmacokinetics of saccharin in man.

1. After intravenous administration of the non-nutritive sweetener, saccharin (10 mg/kg), to normal volunteers; the plasma concentration--time curve fitted a two-compartment open model with a terminal half-life of 70 min. Renal clearance was high and the dose was recovered quantitatively in the urine. The elimination rate and clearance were decreased significantly by concurrent probenecid administration. 2. After oral administration (2 g) more complex and variable plasma concentration--time curves were obtained and these were reflected in the urinary excretion of saccharin. The fraction absorbed was about 0.85 as determined by the recovery in urine and the area under the plasma concentration--time curves. 3. No indication of saturation of renal elimination was found after oral or intravenous doses that were many times the average daily intake.

Physicochemical Properties, Solubility, and Protein Binding of Δ9 -Tetrahydrocannabinol

The rate and extent of glass binding of Δ9 -tetrahydrocannabinol in aqueous solution depend on the surface area and pretreatment of glass and the concentration of the drug. A total of 20 and 40% at 0.1 and 0.05 μg/ml, respectively, was bound to 50-ml volumetric flasks but could be minimized by silyl pretreatment of the glass. The drug rapidly diffused into plastics, and 70–97% was taken up by the rubber closures used for plasma vials. These bindings precluded classical methods of solubility determination, so spectral and particle-size counting determinations, which observed those concentrations at which true solution was terminated, were used. The aqueous solubility was a linear function of both the ethanol concentration (increasing) at constant ionic strength and the square root of the ionic strength (decreasing) at constant ethanol concentration. The salting-out coefficient was of high magnitude and typical solubilities were 2.8 mg/liter in water and 0.77 mg/liter in 0.15M NaCl at 23°. The bindings also precluded the use of the classical methods of equilibrium dialysis and ultrafiltration to determine the protein binding of tetrahydrocannabinol. A method of variable plasma concentrations was devised, so protein binding was determined from the pseudoplasma concentrations of the drug after the separation of the pseudoplasma from the red blood cells added to form pseudoblood with known concentrations of Δ9 -tetrahydrocannabinol. This use of the competition between the high partitioning of drug between red blood cells with plasma water (D = 12.5) and the binding to plasma protein permitted an estimate of 97% binding which was not drug concentration dependent. The spectrophotometric pKa' of Δ9 -tetrahydrocannabinol was 10.6. Δ9 -Tetrahydrocannabinol degraded readily in acid solutions. Subsequent to a rapid loss, the kinetics appeared to be first-order and specific hydrogen-ion catalyzed. Concomitantly, small amounts of Δ8 -tetrahydrocannabinol were produced, as were two GLC observable products, P2 and P3, and the rate of their appearance appeared to parallel the rate of Δ9 -tetrahydrocannabinol degradation. A peak, P1, also appeared almost instantaneously but did not parallel drug degradation.

Pharmacokinetic properties of the beta-adrenergic receptor blocking drugs.

The pharmacokinetic properties of the β-adrenergic receptor blocking drugs have been reviewed and discussed as a possible explanation for the wide range in therapeutic dose. As a general rule, the β-adrenergic receptor blocking action of these compounds is related, in a dose-dependent way, to their concentration in the circulation. The plasma concentrations of these drugs can vary widely after oral administration of the same dose in different individuals. This variation is especially great (up to 20-fold) for those drugs which have a high hepatic clearance (propranolol, alprenolol and oxprenolol), because a large and variable fraction of the drug is eliminated during the process of transfer of drug from the gut to the systemic circulation. Although half-life may be altered by route and duration of administration, it is always relatively short for propranolol, oxprenolol, alprenolol and pindolol (2 to 6 hours) necessitating a relatively short dosage interval. Practolol is unusual in that it is eliminated almost entirely by glomerular filtration and has a significantly longer half-life (9 to 12 hours). Although no data are available, it is likely to give less variable plasma concentrations.