Radioactive characterization of the Pinheiros river bottom sediment

Radionuclide contents were determined in the botton sediment of the Pinheiros river, into which the Instituto de Pesquisas Energéticas e Nucleares (IPEN) has been continuously discharging low level radioactive liquid effluents. The results showed that the activity of natural radionuclides and the activity of (137)Cs found in the sediment were within the range of the expected baskground for the region. (60)Co was the only other artificial radionuclide detected, with concentrations ranging from 0.20 to 0.85 Ba per kilogram dry weight, at some points of the river.

Transdermal delivery of metoprolol. II: In-vitro skin permeation and bioavailability in hairless rats.

The absolute bioavailability of metoprolol (MP) was evaluated following oral and transdermal administration in hairless rats. The absolute bioavailability of MP following oral administration was 3.48 +/- 1.73%, indicating that MP is subject to extensive hepatic first-pass metabolism. Transdermal delivery of MP, via an adhesive delivery device, resulted in a bioavailability of 30.07 +/- 4.84%, indicating that the transdermal delivery of MP can significantly increase systemic bioavailability compared with oral administration. Preliminary skin irritation studies indicated that neither MP nor the adhesive used in the device caused any appreciable skin irritation in the hairless rats.

A preliminary pharmacokinetic evaluation of the antimetastatic immunomodulator swainsonine: clinical and toxic implications.

The pharmacokinetics of swainsonine (SW) was investigated in mice after intravenous administration of 3 micrograms/ml. The time course of SW blood levels followed a three-compartment open pharmacokinetic model which consisted of biphasic distribution, and a rapid elimination phase (terminal half-life, 31.6 min). After completion of the distribution, SW was widely distributed to the extravascular space (Vss, 22ml; Vd, 33ml). Free fractions of this substance were indistinguishable from unity, indicating little or no protein binding. The rate-limiting step in the elimination of SW from the body appears to be the slow return from the deep compartment into the central one. Accordingly, SW blood levels may be low and yet significant amounts of this agent may be present in different body organs and tissues. A comparison of SW tissue levels indicates that the highest amounts appeared in the bladder, kidney, and thymus, (3.8 0.5, and 2.2 nmoles/g wet wt) with the lowest levels consistently appearing in the brain (< 0.1 nmoles/g wet wt). Hence, this study suggest that: 1) SW has high affinity for the thymus, which is in part consistent with its previously published immunomodulatory action; 2) SW should be infused for at least 2 1/2 hrs for its concentration to approach a plateau (this is based on the short half-life of SW and its time to steady state); and 3) CNS toxicity may be dose-limiting and not be present at SW levels preventing metastasis.

Effect of experimental hyperthyroidism on atropine pharmacokinetics in sheep.

Atropine sulfate (0.02 mg/kg, i.m.) was administered to normal sheep and to sheep with experimentally induced hyperthyroidism. Serum and urine concentrations of atropine measured by radioimmunoassay were monitored over an 8-h period. The time to reach maximum serum concentration was similar in both hyperthyroid and normal sheep. A comparison between normal and hyperthyroid sheep indicated that the atropine absorption rate was not changed, but its rate of elimination was significantly greater in hyperthyroid sheep (p less than 0.01). Hyperthyroidism resulted in significant decreases in atropine (p less than 0.05), MRT (p less than 0.01), AUC (p less than 0.01) and an increase in C1/F (p less than 0.01) when compared to atropine kinetics of normal sheep.

Excretion of tolbutamide metabolites in young and old subjects.

Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.

Unusual absorption profile of phenytoin in a massive overdose case.

The pharmacokinetics of phenytoin was evaluated in a nonepileptic adult man after the ingestion of an undetermined amount of the drug following an apparent suicide attempt. A serum phenytoin concentration of 45 micrograms/mL was observed on admission 12 hours after ingestion. Phenytoin concentrations steadily increased, reached a maximum of 114 micrograms/mL four days later, then fluctuated at about 100 micrograms/mL for a week, and slowly declined to undetectable levels within the following week. At 96.5 micrograms/mL, the unbound serum concentration was 2.5 times that observed in therapeutic drug concentrations. Computer fitting of the data indicated that the Michaelis-Menten constants, apparent volume of distribution, and renal clearance of phenytoin were consistent with those parameters reported after therapeutic doses. However, phenytoin absorption was best described by parallel first- and zero-order rate processes, with the latter proceeding for as long as two weeks following drug ingestion. This protracted absorption appears to be a result of the presence of a large concretion of phenytoin in the gastrointestinal tract, having a slow disintegration and dissolution attributable to the limited solubility of the drug in the gastrointestinal tract and to the patient's diminished intestinal motility.

Comparative efficacy and safety of immediate-release and controlled-release hydralazine in black hypertensive patients.

Twenty-nine black hypertensive patients were randomized to treatment with controlled-release hydralazine capsules administered BID or QD, or immediate-release hydralazine tablets administered TID, for at least four weeks in a double-blind, parallel study. Hydralazine was begun after a two-week to four-week period in which blood pressure was not adequately controlled with diuretics alone. Each patient initially received 75 mg/day of the assigned drug. The dosage could be increased to 150 or 300 mg/day at weekly intervals if sitting diastolic blood pressure was not adequately controlled (greater than 90 mmHg). A beta-blocker (80 mg/day of nadolol) was added only for patients who had beta-blocker-responsive adverse effects that could not be controlled otherwise. Nine patients were considered unevaluable because of protocol violations or withdrawal from the study before completion of four weeks of treatment, primarily because of adverse effects. Twenty patients were included in the efficacy evaluation. Controlled-release hydralazine BID produced statistically significant mean falls from baseline in sitting diastolic blood pressure and in standing systolic blood pressure and an almost significant drop in standing diastolic blood pressure. Although the other two treatment groups also had substantial falls in all blood pressure measurements, the changes from baseline were not statistically significant. No significant difference in response was noted between patients who received a beta-blocker and those who did not. There were no statistically significant differences among the three treatment groups in incidence and severity of adverse effects or electrocardiographic abnormalities. A statistically, but not clinically, significant fall in hemoglobin, hematocrit, and red blood cell count was observed in all three treatment groups.

Nomogram for bretylium dosing in renal impairment.

Bretylium (Bretylol), an antiarrhythmic agent, is currently being used in the prophylaxis and treatment of patients with life-threatening ventricular fibrillation and tachycardia not responsive to conventional therapy. Because bretylium has a delayed onset of action that commonly causes hypotension and may increase ventricular irritability, its use in patients (especially patients with renal impairment) must be exercised with caution. Our results show that the maximum plasma concentration (Cmax) observed at the end of bretylium infusion, when normalized to the dose, increases significantly as renal function diminishes. Significant reductions in renal and total body clearance of bretylium have been observed in patients with renal insufficiency. In order to minimize the risk of potential toxicity following multiple dosing in such patients, dosage adjustments are necessary. Based on correlations developed between the total body clearance of bretylium and renal function, we present a nomogram herein that can be effectively used for adjusting the dosage of bretylium in patients with renal impairment.

Alcohol and the steady-state disposition kinetics of methadone in rats.

In order to examine whether alcohol alters the steady-state disposition of chronic or acute doses of methadone, three groups (N = 5 each) of male Sprague-Dawley rats were administered oral doses of methadone daily for 14 days. Group 1 received oral doses of alcohol twice daily whereas groups 2 and 3 were given isocaloric sucrose. Water was provided ad libitum and food consumption was controlled by paired feeding. On day 15, all of the animals were given the last dose as C14 methadone. Group 2 received a concurrent dose of alcohol but groups 1 and 3 received isocaloric sucrose. Blood was drawn at timed intervals for 48 hr. Methadone and its major metabolite (M1) in plasma were separated by thin-layer chromatography and underwent liquid scintillation counting. The elimination half-life (t1/2, beta) and the area under the plasma concentration-time curve (AUC) of methadone and M1 were determined in all of the three groups. Group 1 demonstrated the smallest AUC and the shortest t1/2 for methadone and M1 (p less than .05). Group 2 displayed the highest amount of unchanged methadone (p less than .05) in the first 2 hr after administration, but its t1/2 and AUC of methadone and M1 were not significantly different from those of group 3. These data may help explain why there is a high incidence of heavy drinking among methadone-maintained patients.

Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure.

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.

Bretylium kinetics in renal insufficiency.

Bretylium kinetics were examined in patients with varying degrees of renal impairment after a single intravenous dose of bretylium tosylate. Maximum plasma concentrations achieved at the end of the infusion, when normalized to the dose, correlated strongly with creatinine clearance. Drug disposition from plasma was biexponential, with a short distributive phase, but drug elimination was reduced, especially in patients with creatinine clearance below 30 ml/min X 1.73 m2. There was reduction in renal and total clearance and prolongation of t 1/2, with deteriorating renal function. In one patient who was reevaluated after a year, there was 76% reduction in the total clearance, corresponding to 43% deterioration of renal function. The difference of 33% between these values is due to a reduction of nearly 36% in volume of distribution, caused by the further deterioration of the renal function. Six-hour hemodialysis procedure on two anephric patients, resulted in an apparent one- to threefold increase in the computed bretylium clearance during dialysis, but the fraction of the total body load eliminated during the same period was not proportionally significant. The strong linear relationships between renal and total clearance, beta, and the creatinine clearance, may be helpful in adjusting dosage regimens for bretylium in patients with renal dysfunction.

Effects of total plasma concentration and age on tolbutamide plasma protein binding.

Tolbutamide plasma protein binding at different total tolbutamide concentrations was determined in 44 healthy, nonsmoking, drug-free men from 23 to 87 yr old. The data showed that unbound drug increased with total tolbutamide plasma concentration and with age, but that neither the binding equilibrium constant nor the number of binding sites correlated with age. The increase in unbound fraction with age could be partially explained by the decrease in albumin concentration in elderly subjects. Results of multiple linear regression analysis indicated that, although age had a considerably greater influence than albumin concentration, total tolbutamide concentration was the most important determinant of the unbound fraction. Thus, both age and total plasma concentration may affect tolbutamide kinetics.

Digoxin pharmacokinetics in congestive heart failure.

The steady-state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right-sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24-hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half-life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P less than 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.

Pharmacokinetics of nicotine in rats after single-cigarette smoke inhalation.

The amount of nicotine absorbed following cigarette smoke inhalation was evaluated by comparing the area under the plasma concentration--time curve and urinary recovery with those observed after its intravenous injection to rats. Nicotine was adsorbed rapidly, with the maximum plasma concentration occurring immediately after cessation of cigarette smoke exposure. On the average, 68% of the nicotine delivered to the inhalation chamber was absorbed. The absorption and elimination of nicotine, as well as the formation and elimination of its metabolites, followed first-order kinetics, and the derived pharmacokinetic parameters were similar to those observed after the intravenous administration of nicotine.

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.

Effect of ethanol pretreatment on the pharmacokinetics of nicotine in rats.

The pharmacokinetics of nicotine was compared in male Fischer-344 rats pretreated with an ethanol or a sucrose solution for 12.5 days. The animals received either ethanol at doses of 4 g/kg/day for 7 days followed by 8 g/kg/day for 5.5 days or daily doses of an isocaloric-isovolumetric sucrose solution for 12.5 days by gastric intubation. On the fourteenth day, a 0.4 mg/kg dose of [methyl-14C]nicotine was injected i.v. to both groups, and blood samples were collected at timed intervals for 30 hr. Nicotinine and its metabolites in plasma were separated by thin-layer chromatography and quantitated by liquid scintillation counting. The plasma levels of total radioactivity, nicotine, cotinine and other polar metabolites were significantly lower in the ethanol as compared to the sucrose-treated rats. Ethanol pretreatment produced no changes in the hybrid rate constants describing the biphasic decline of plasma nicotine concentration but its apparent volume of distribution and total plasma clearance were increased by 45% (P less than .05) suggesting that ethanol may alter the distribution of nicotine. The apparent volume of distribution of cotinine and its rate of production also were significantly increased indicating an ethanol-related induction of this major metabolite of nicotine.

Comparison of steady state phenytoin metabolism in alcoholic immediately after drinking ceases and three weeks later.

Chronic use of alcoholic beverages as found in American alcoholics changes the rate of phenytoin metabolism but the prevalence of this change is not known because too few patients have been studied and no observations exist on its persistence after drinking ceases. This study reports observations in four alcoholic patients.