Furosemide binding to human albumin and plasma of nephrotic children.

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.     

The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man.

The effects of insulin on the renal handling of sodium, potassium, calcium, and phosphate were studied in man while maintaining the blood glucose concentration at the fasting level by negative feedback servocontrol of a variable glucose infusion. In studies on six water-loaded normal subjects in a steady state of water diuresis, insulin was administered i.v. to raise the plasma insulin concentration to between 98 and 193 muU/ml and infused at a constant rate of 2 mU/kg body weight per min over a total period of 120 min. The blood glucose concentration was not significantly altered, and there was no change in the filtered load of glucose; glomerular filtration rate (CIN) and renal plasma flow (CPAH) were unchanged. Urinary sodium excretion (UNaV) decreased from 401 plus or minus 46 (SEM) to 213 plus or minus 18 mueq/min during insulin administration, the change becoming significant (P smaller than 0.02) within the 30-60 min collection period. Free water clearance (CH2O) increased from 10.6 plus or minus 0.6 to 13 plus or minus 0.5 ml/min (P smaller than 0.025); osmolar clearance decreased and urine flow was unchanged. There was no change in plasma aldosterone concentration, which was low throughout the studies, and a slight reduction was observed in plasma glucagon concentration. Urinary potassium (UKV) and phosphate (UPV) excretion were also both decreased during insulin administration; UKV decreased from 66 plus or minus 9 to 21 plus or minus 1 mueq/min (P smaller than 0.005), and tupv decreased from 504 plus or minus 93 to 230 plus or minus 43 mug/min (P smaller than 0.01). The change in UKV was associated with a significant reduction in plasma potassium concentration. There was also a statistically significant but small reduction in plasma phosphate concentration which was not considered sufficient alone to account for the large reduction in UPV. Urinary calcium excretion (UCaV) increased from 126 plus or minus 24 to 200 plus or minus 17 mug/min (P smaller than 0.01). These studies demonstrate a reduction in UNaV associated with insulin administration that occurs in the absence of changes in the filtered load of glucose, glomerular filtration rate, renal blood flow, and plasma aldosterone concentration. The effect of insulin on CH2O suggests that insulin's effect on sodium excretion is due to enhancement of sodium reabsorption in the diluting segment of the distal nephron.     

Comparison of Plasma Protein Binding of Basic Drugs in Black and White Individuals

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.     

Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man.

Propylthiouracil (PTU) inhibits peripheral deiodination of thyroxine (T4) and triiodothyronine (T3) and decreases the metabolic effectiveness of T4 in animals. To assess the effect of PTU on extrathyroidal conversion of T4 to T3 in man, 15 studies were performed in athyreotic patients treated with 100 or 200 mug of L-T4 daily for 1 mo before the addition of PTU, 250 mg every 6 h for 8 days. serum T3, T4, and thyrotropin (TSH) were measured daily by radioimmunoassay; serum TSH response to 500-mug thyrotropin-releasing hormone (TRH) was measured before and on the last day of giving PTU. On the 100-mug LT4 dose, serum T3 fell from 120 plus or minus 5 (SE) to 83 plus or minus 6 ng/dl (P less than 0.005) with return to 113 plus or minus 5 ng/dl after stopping PTU; serum T4 (4.5 plus or minus 0.3 mug/dl) did not change. Similar results were seen in patients taking 200 mug of L-T4 daily. On the 100-mug dose of L-T4 the fall in T3 was accompanied by a reciprocal rise in serum TSH to 195 plus or minus 33% of initial concentration (P less than 0.01) with return to 104 plus or minus 8% after PTU. The serum TSH response to TRH (DELTAMUU/ml over base line) was greater during PTU therapy than during the control period. On 100-mug L-T4 DELTA TSH rose from 64 plus or minus 19 to 101 plus or minus 23 muU/ml (P less than 0.005). Expressed as percent of base-line TSH concentration, TSH rose from 140 plus or minus 52 to 280 plus or minus 44% (control vs. PTU) at 15 min, 265 plus or minus 72 to 367 plus or minus 63% at 30 min, 223 plus or minus 54 to 313 plus or minus 54% at 45 min, 187 plus or minus 45 to 287 plus or minus 51% at 60 min, and 145 plus or minus 22 to 210 plus or minus 28% at 120 min after TRH. The data suggest that PTU blocks extrathyroidal conversion of T4 to T3, thus increasing pituitary TSH secretion and augmenting the TSH response to TRH.     

Single-dose ceftriaxone kinetics in functionally anephric patients

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.     

Theophylline pharmacokinetics in normal elderly subjects

The effect of age on theophylline kinetics was examined in six normal young men and six elderly men. There were no age-associated differences in theophylline volume of distribution, total clearance, or t1/2. The unbound fraction of theophylline was significantly raised in the elderly (mean 77.7% vs. 62.3%, p less than 0.001) and was correlated with the serum albumin level (r = -0.7, p less than 0.01). Theophylline nonrenal clearance was not changed, but the total unbound clearance was significantly reduced in the elderly subjects as compared with the young ones (mean 0.744 vs. 1.085 ml/min/kg, p less than 0.05). Creatinine clearance was reduced in the elderly and was significantly correlated with unbound renal clearance (r = 0.6, p less than 0.04). There were no age-related differences in the urinary excretion of theophylline, 1-methyluric acid, 3-methylxanthine, or 1,3-dimethyluric acid. However, significant reduction in unbound renal theophylline clearance (p less than 0.002) as well as the unbound metabolic clearance of 1,3-dimethyluric acid (p less than 0.03), 3-methylxanthine (p less than 0.04), and 1-methyluric acid (p less than 0.02) were observed in the elderly subjects. These observations indicate that both renal and metabolic elimination processes for theophylline are less active in the normal elderly.     

The effects of age and liver disease on the disposition and elimination of diazepam in adult man.

This study investigates the separate effects of age and hepatocellular liver disease on the disposition and elimination of diazepam (Valium) in man. The drug was given either by rapid intravenous injection (0.1 mg/kg) or orally (10 mg) to 33 normal volunteers rnaging in age from 15 to 82 yr as well as to 9 individuals with alcoholic cirrhosis, 8 with acute viral hepatitis, and 4 with chronic active hepatitis. In the normal individuals, the terminal plasma half-life of diazepam, (t 1/2 (B)) exhibited a striking age-dependence; at 20 yr the t 1/2 (beta) was about 20 h, but it increased linearly with age to about 90 h at 80 yr. The plasma clearance of diazepam in the majority of the normal subjects was between 20 and 32 ml/min and showed no significant age-dependence. Cigarette smoking did not affect the half-life or the clearance. Additionally, neither the plasma binding (97.4 plus or minus 1.2%, mean plus or minus SD) nor the blood/plasma concentration ratio (0.58 plus or minus 0.16) of diazepam showed any age-related changes (P greater than 0.05). By contrast, analysis of the intravenous data according to a two-compartment open model indicated that both the initial distribution space (V1) and the volume of distribution at steady state [Vd(ss)] of diazepam increased linearly with age (P less than 0.005). The increase in Vd(ss) was secondary to the change in V1. It appears then that the prolongation of t 1/2 (beta) of diazepam with age is primarily dependent on an increase in the initial distribution volume of the drug. The plasma concentration/time course of the metabolite, desmethyldiazepam, was also affected by age. In older individuals, the initial presence and the peak values of desmethyldiazepam were observed later and the metabolite was present in lower concentrations. Despite the profound prolongation of t 1/2 (theta) with age, the constancy of diazepam clearance indicates that drug plasma concentrations will not accumulate any more in the old than the young, and chronic dosage more in the old than the young, and chronic dosage modifications based on pharmacokinetic considerations are unnecessary. Data obtained in patients with liver disease were compared with those found in age-matched control groups. Patients with cirrhosis showed a more than twofold prolongation in the half-life of diazepam (105.6 plus or minus 15.2 vs. 46.6 plus or minus 14.2 h, P less than 0.001).     

Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia.

Teniposide, a widely used investigational anticancer drug, is extensively bound to plasma proteins (greater than 95%). The present study evaluated the clearance and pharmacodynamics of total and unbound teniposide in patients with acute lymphocytic leukemia who were either in first complete remission or who had relapsed and achieved a subsequent complete remission. When compared to values of patients in first remission, the mean total systemic clearance of teniposide in relapsed patients was significantly lower at the time remission reinduction therapy was initiated, but increased to values greater than first remission patients after a subsequent remission was achieved. However, the mean clearance of unbound teniposide (ml/min/m2) was 3-fold lower in relapsed patients during reinduction therapy (1224 vs. 4261, P less than .0001), and improved but remained low after these patients achieved a subsequent remission (1965, P = .025). Changes in plasma protein binding accounted for the increase in total clearance when unbound clearance decreased. Continuous therapy with L-asparaginase was the major treatment difference in those patients with hypoalbuminemia and lower clearance of unbound teniposide. In 15 evaluable patients in complete remission, there was a statistically significant (P = .039) linear correlation between the percentage decrease in white blood cell count and the systemic exposure (AUC) to unbound teniposide, with higher exposure associated with a greater decrease in white blood cell count. There was not a significant correlation between the percent decrease in white blood cell count and the dosage given or the systemic exposure to total teniposide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys.

The effect of variations in plasma protein binding on the renal excretion of cefonicid was assessed by using isolated perfused rat kidneys. Cefonicid exhibits preferential binding ex vivo to human serum albumin (HSA), as opposed to bovine serum albumin (BSA), and is eliminated mainly by tubular secretion, a process that was reported to be dependent on the total drug concentration. This contradicts previous studies with antimicrobial compounds and other drugs of low renal extraction in which the unbound drug concentration was shown to be the driving force for carrier-mediated tubular transport. To clarify this discrepancy, we performed perfusion studies by using 6% BSA at initial concentrations of 200 micrograms/ml (n = 6) and 20 micrograms/ml (n = 9) and in a combination of 4% BSA plus 2% HSA at initial concentrations of 200 micrograms/ml (n = 4). The excretion ratio [ER = CLR/(fu x GFR)] of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with the total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance increased significantly in the 4% BSA-2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport and secretion was dependent on the unbound cefonicid concentration. As a result, changes in plasma protein binding as a result of drug interactions or disease states could significantly influence the tubular transport capability of compounds with low renal extraction.     

Polymorphic acetylation procainamide in man.

N-Acetylprocainamide (NAPA) and procainamide plasma and urine concentrations were determined by thin-layer chromatography (TLC) densitometry in people of known acetylator phenotype (dapsone phenotyping) taking procainamide for more than 3 days. The plasma NAPA/procainamide ratio 3 hr after the last dose for fast acetylators (mean plus or minus SD) is 1.8 plus or minus 0.59 (N equal to 8) and for slow acetylators, 0.61 plus or minus 0.09 (N equal to 6) P smaller than 0.001). The renal clearance of NAPA averaged 1.2 times the simultaneously measured endogenous creatinine clearance, whereas procainamide clearance was approximately double the creatinine clearance. There was no difference between slow and rapid acetylators in the renal clearance of either drug or the urine pH, indicating that the difference in plasma NAPA/procainamide ratios between these two groups is due to differences in their rates of acetylation. Therefore, procainamide is probably acetylated by the polymorphic N-acetyltransferase in man. Reflecting the blood level differences, the NAPA/procainamide ratio in urine (collected 99 to 180 min after last dose) was found to be higher in rapid than in slow acetylators. The plasma protein binding of NAa and of procainamide are similar. Since NAPA seems to have an antiarrhythmic potency similar to procainamide, NAPA probably contributes to the antiarrhythmic activity of procainamide therapy, especially in genetic rapid acetylators.     

Pharmacokinetics and dynamics of furosemide in the newborn piglet

Furosemide was administered as either an i.v. bolus (6 mg/kg) or primed continuous infusion (4 mg/kg/hr) with quantitative fluid replacement to 10 3-day-old and 9 18-day old piglets. Total and unbound plasma as well as urinary furosemide concentrations were measured for up to 6 hr and drug disposition and renal sodium excretory dynamics were compared at the two ages. The plasma clearance of furosemide was concentration-independent over the range studied (0.1-10 mg/l). Steady-state volume of distribution and unbound fraction of furosemide in plasma were both considerably higher in the younger piglets (618 +/- 320 vs. 201 +/- 71 ml/kg, p less than .01 and 0.22 +/- 0.08 vs. 0.06 +/- 0.02 ml/kg, p less than .001, respectively) while unbound secretory clearance was several-fold lower in this age group (49.2 +/- 23 vs. 107 +/- 55 ml/min/kg, P less than .01). A log-logistic equation was fitted to sigmoidal plots of sodium excretion rate vs. log furosemide excretion rate. While basal response and slope parameters did not differ significantly, maximal response and stimulus required for half-maximal response were both reduced in the younger piglets (0.70 +/- 0.24 vs. 1.18 +/- 0.30 mmol/min and 0.06 +/- 0.04 vs. 0.14 +/- 0.06 mumol/min, respectively, P less than 0.05). Thus, younger piglets were more sensitive to the natriuretic effects of the drug. While term piglets were useful for studying the maturation of protein binding and renal drug excretory processes for furosemide, drug disposition was not comparable to that in human premature infants because of the higher secretory capability of the piglet.     

Elimination of amphotericin B in impaired renal function

The influence of impaired renal function on the steady-state plasma clearance of amphotericin B was determined in seven patients with creatinine clearances ranging from zero to normal. Contrary to previous reports, steady-state plasma concentrations of total drug were lower in uremic patients than in patients with normal renal function. Total plasma clearance of amphotericin B ranged from 16.7 to 39.9 ml/min, correlated directly with the plasma creatinine concentration, and correlated inversely with the creatinine clearance. Urinary excretion of unchanged drug accounted for less than 10% of the dose. In 10 healthy subjects, mean percent of amphotericin B unbound in plasma was 3.55 +/- 0.32 (SD). Binding was determined in a further group of 10 uremic patients. Mean unbound percent (4.15 +/- 0.73, SD) was higher than in the healthy subjects, and the binding ratio (molar concentration of bound to unbound drug) correlated weakly with the creatinine clearance. This suggests that plasma clearance of unbound amphotericin B and, therefore, steady-state plasma concentrations of unbound drug are not affected by renal impairment, and that dosage requirements will be overestimated if based on measurements of total drug plasma concentration.     

Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and warfarin metabolism.

The influence of sulfamethizole on the metabolism of diphenylhydatoin (DPH) tolbutamide, and warefarian is examined. In 8 patients DPH means half-life (T/2) increased from 11.8 plus or minus 3.6 hr to 19.6 plus or minus 5.2 hr and mean metabolic clearance rate (MCR) decreased from 43.7 plus or minus 16,8 to 28.1 plus or minus 9.1 ml/min durus or minus 1.2 to 9.2 plus or minus 1.2 hr MCR decrease from 17.0 plus or minus 5.4 to 10.5 plus or minus 1.2 ml/min. In 2 patients warfarin T/2 increased fron an average of 64.7 to 92.7 hr and MCR decreased from 1.65 ml/min to 1.05 ml/min. In 4 patients on long-term DPH treatment after 1 wk on sulfamethizole inhibits hepatic metabolism of DPH, tolbutamide, and warfarin.     

Adipose tissue cellularity and lipolysis. Response to exercise and cortisol treatment.

Male rats a 5 wk of age were subjected to 13 wk of intensive treadmill running to study the effect of exercise on adipose tissue cellularity and lipolysis. Untrained controls of the same age remained sedentary in their cages for the duration of the experiment. Adipocyte numbers were similar in eqidiymal fat pads from trained and untrained rats (12.7 plus or minus 1.3 X 10(6) vs. 15.3 plus or minus 1.3 X 10(6) cells/pad), however trained rats had smaller fat pads containing smaller cells (0.09 plus of minus 0.01 vs. 0.20 plus or minus 0.04 mug triglyceride/cell). Adipocytes from trained rats possessed greater epinephrine-sensitive lipase activity than sedentary rats on a per cell, per milligram protein, per gram adipose tissue, or per fat pad basis. Although the smaller cells of the trained rats had greater epinephrine-sensitive lipase activity than the larger cells of the untrained rats, lipolysis was positively correlated with cell size within both treatment groups. Cortisol treatment of intact animals did not significantly affect in vitro adipose tissue lipolysis. The results of this study indicate that exercise training increased the potential of adipose tissue cells to release free fatty acids in response to epinephrine stimulation. Exercise training initiated at 5 wk of age had only a small effect on adipose tissue cell numbers but significantly decreased cell size.     

Chloramphenicol Pharmacokinetics in Hospitalized Patients

The apparent body clearance of chloramphenicol was investigated in 21 hospitalized adult patients on 27 occasions. Apparent body clearance was found to be significantly lower (1.99 +/- 1.49 ml/min per kg) in patients with total serum bilirubin concentrations of >1.5 mg/100 ml than in patients with serum bilirubin concentrations of 相似文献   

Digitalis toxicity during acute hypoxia in intact conscious dogs.

Intact, conscious dogs were studied under normal and hypobaric conditions to assess the influence of acute hypoxia on the ability of the animals to tolerate ouabain. Animals were made acutely hypoxic by exposure to hypobaric conditions in a chamber maintained at 446 mm Hg. The ability of the dogs to tolerate ouabain was determined by administering intravenously 7.5 mug/kg of the drug as a loading dose followed by infusion at a rate of 3.0 mug/kg/min to an end point consisting of the development of ventricular or atrioventricular junctional tachycardia. Eight dogs, each acting as its own control, were studied under normoxic and acutely hypoxic conditions. During hypoxia, mean arteriol pO2 decreased to 39 plus or minus 1 (S.E.) mm Hg from 80 plus or minus 1 mm Hg at sea level (P less than .001). The cumulative toxic dose of ouabain was modestly but significantly less (P less than .05) during acute hypoxia (71.7 plus or minus 4.3 mug/kg) compared with normoxic (79.2 plus or minus 4.1 mug/kg) conditions. In these experiments a marked hyperventilation response to ouabain was observed just before onset of toxicity which resulted in a pronounced rise in mean arterial pH (normoxia: 7.39 plus or minus 0.01 to 7.72 plus or minus 0.01; hypoxia: 7.48 plus or minus 0.01 to 7.71 plus or minus 0.04) and fall in pCO2 (normoxia: 41 plus or minus 1 to 14 plus or minus 1 mm Hg; hopoxia: 34 plus or minus 1 to 16 plus or minus 2 mm Hg). Ouabain-induced increases in systemic arterial pressure were comparable in normal and acutely hypoxic animals. Thus, acute hypoxia in unanesthetized dogs exposed to hypobaric conditions results in a decrease of only 10% in the ouabain dose required to produce cardiac arrhythmias, and toxic doses of ouabain produce a striking respiratory alkalosis.     

The effect of estrogen on the lipoprotein lipase activity of rat adipose tissue.

The effect of 17beta-estradiol or progesterone administration on adipose tissue lipoprotein lipase activity was studied in male and ovariectomized female rats. Lipoprotein lipase activity was measured in acetone-ether-extracted preparations of adipose tissue with doubly labeled (14C-fatty acid, 3H-glyceryl) chylomicron triglyceride as substrate. Administration of 17beta-estradiol to male rats lowered adipose tissue lipoprotein lipase activity from 8.22 plus or minus 1.8 U/g (1 U = 1 mumol triglyceride hydrolyzed per h) to 4.96 plus or minus 0.5 U/g in the treated group. Ovariectomy increased adipose tissue lipoprotein lipase activity from 10.4 plus or minus 1.8 U/g in controls to 22.7 plus or minus 4.3 U/g. 17beta-Estradiol administration to ovariectomized rats cuased a marked fall in adipose tissue lipoprotein lipase activity: 17beta-estradiol (2.5 mug/day) lowered the enzyme activity to 9.00 plus or minus 1.2 U/g, whereas 25 mug/day further decreased lipoprotein lipase activity to 3.2 plus or minus 0.6 U/g. Blood triglyceride levels increased from 0.8 plus or minus 0.05 mumol/ml in ovariectomized rats to 1.4 plus or minus 0.09 mumol/ml in 25 mug/day 17beta-estradiol-treated rats. Progesterone administration did not affect adipose tissue lipoprotein lipase activity in either male or ovariectomized rats. Heart and lung lipoprotein lipase activity was unaffected by hormone treatment. We suggest that the rise in blood triglyceride concentrations, which accompanies high palsma estrogen levels, could be due to the marked inhibition of adipose tissue lipoprotein lipase activity.     

Kinetics of prednisolone and endogenous cortisol suppression in the elderly

The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.     

Effect of Food on the Pharmacokinetics and Pharmacodynamics of Torsemide

The effect of food on the bioavailability, pharmacokinetics, and pharmacodynamics of oral torsemide was examined in a group of 14 healthy male volunteers. Administration of torsemide with a standard high-fat, high-carbohydrate breakfast resulted in a decrease in absorption rate (fed: C(max) 988 plus minus 269 ng ml(minus sign1), T(max) 1.50 plus minus 0.64 h; fasting: C(max) 1466 plus minus 202 ng ml(minus sign1), T(max) 0.89 plus minus 0.37 h) but no change in the extent of absorption (fed: AUC 3424 plus minus 841 h ng ml(minus sign1); fasting: AUC 3357 plus minus 859 h ng ml(minus sign1)) or the amount of drug excreted unchanged (fed: % dose 23.5 plus minus 4.3; fasting: % dose 23.7 plus minus 6.2). Elimination half-life and renal clearance were unchanged. These minor alterations in the pharmacokinetics of the drug were not reflected by a change in either the pharmacodynamic relationship between urinary sodium and drug excretion rates or the cumulative amount of electrolytes and urine excreted. The diuretic effect of torsemide will be consistent regardless of drug administration relative to food intake.     

Naproxen kinetics and disease activity in rheumatoid arthritis: a within-patient study

The effects of rheumatoid arthritis disease activity on the pharmacokinetics of the highly albumin-bound nonsteroidal anti-inflammatory drug naproxen were studied in six patients during chronic therapy. In the same patients, kinetics during active disease were compared with those in improvement. Active disease is commonly associated with hypoalbuminemia: 30 +/- 4 gm/L vs. 41 +/- 2 gm/L (mean +/- SD) at the time of improvement. Total naproxen concentrations were significantly lower in active disease, together with a larger apparent volume of distribution (10.6 +/- 1.8 L vs. 8.4 +/- 1.3 L; P less than 0.05) and total body clearance (0.79 +/- 1.8 L/hr vs. 0.59 +/- 0.14 L/hr; P less than 0.001). Peak unbound naproxen concentrations were 29% +/- 19% (P less than 0.05) lower at the time of improvement. The unbound clearance was found diminished during active disease (390 +/- 277 L/hr) in comparison with improvement (488 +/- 343 L/hr; P less than 0.05). Clinical implications of the alterations in naproxen kinetics induced by polyarticular inflammation in patients with rheumatoid arthritis are discussed.