Rebecca S. Sloan

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40‐mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

Vancomycin kinetics during continuous ambulatory peritoneal dialysis

To establish therapeutic guidelines for vancomycin usage in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied single‐dose kinetics of vancomycin in CAPD patients. Vancomycin was studied after a 10‐mg/kg dose was given intravenously (VAN‐IV) or intraperitoneally (VAN‐IP). VAN‐IV provided a plasma concentration above 10 mg/l at 12 hr, with a t½ of 81 hr. When VAN‐IP was given, 65% was absorbed; peak plasma concentrations were only 6.3 mg/l, and t½ was 66 hr. CAPD accounted for only 15% to 17% of total body clearance in both groups. The kinetic principle of superposition was used to predict plasma concentrations after repeated VAN‐IP doses. A model with once‐a‐day dosing predicted that a loading dose of 30 mg/kg followed by 7 mg/kg would achieve steady‐state plasma concentrations of 11 to 14.8 mg/l. Another model with vancomycin in each exchange predicted that a loading dose of 30 mglkg followed by 1.5 mg/kg would provide plasma concentrations in excess of 10 mg/l at 180 hr. These data should be useful in vancomycin treatment of CAPD patients who have nonperitoneal gram‐positive bacterial infections, as well as those who have peritonitis.

Multiple‐dose ciprofloxacin kinetics in normal subjects

To determine multiple‐dose kinetics of the quinoline carboxylic acid derivative ciprofloxacin, we gave 12 normal subjects ciprofloxacin, 250 mg by mouth every 12 hr for 13 doses. Plasma concentrations were measured by HPLC after the first, seventh, and thirteenth doses. Peak and trough plasma concentrations were measured daily. Ciprofloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum serum concentrations about 1 hr after dosing. Ciprofloxacin elimination t½ increased from 3.71 hr after the first dose to 6.51 hr after the thirteenth dose (P < 0.05). Apparent plasma clearance decreased from 0.823 to 0.629 l/kg/hr because of decreased nonrenal clearance. Drug cumulation did not occur throughout the experiment. We conclude that concentrations of ciprofloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be achieved in plasma and that controlled clinical trials of ciprofloxacin efficacy in selected systemic infections are warranted.

Recovery from Aminoglycoside Nephrotoxicity with Continued Drug Administration

To examine the nephrotoxicity of prolonged gentamicin administration compared to the effect obtained when a less toxic aminoglycoside is substituted during the course of treatment, we gave gentamicin (67.5 mg/kg per day) to rats for 21 days, gentamicin for 14 days followed by either netilmicin or tobramycin for 7 days, or gentamicin for 14 days followed by saline diluent. After initial tubular, necrosis, the animals recovered from renal injury whether the drug was continued or discontinued or another drug was substituted. These data are consistent with the observation that regenerating renal epithelium is resistant to continued or additional nephrotoxic insults. These findings suggest that improvement in renal function during aminoglycoside therapy cannot necessarily be attributed to the substitution of another aminoglycoside or other therapeutic interventions.

Effects of vancomycin on renal function in rats.

To assess the effects of vancomycin on the kidney, we gave rats doses of 10, 50, 100, 200, and 400 mg/kg per day. Creatinine clearance and urine protein excretion did not differ significantly from the control values. Urine osmolality was unchanged. Mild histological changes occurred in rats given the highest dose. We conclude that although histopathological changes occurred at high doses, vancomycin does not alter renal function in rats.

Protection from Gentamicin Nephrotoxicity by Cephalothin and Carbenicillin

In rats, cephalothin exerts a protective effect upon the nephrotoxicity of gentamicin. To examine the possibility that this effect is also observed with carbenicillin, we gave the following (milligrams per kilogram) to rats daily for 14 days: gentamicin alone, 60; gentamicin plus cephalothin, 100, 500, or 1,000; gentamicin plus carbenicillin, 50, 100, 250, 500, or 1,000. A 500-mg/kg dose of cephalothin afforded significant partial protection from gentamicin nephrotoxicity, as did a 100-mg/kg dose of carbenicillin. Increasing doses of either drug failed to increase protection. The data suggest that in rats not only does carbenicillin afford some protection from gentamicin nephrotoxicity, but also that it does so at a lower dose than cephalothin. These findings may in part explain the divergent observations regarding the nephrotoxicity of cephalothin-gentamicin combination therapy in rats and humans.

Cefazolin and cephalexin kinetics in continuous ambulatory peritoneal dialysis

We studied single‐dose cefazolin (CFZ) and cephalexin (CPX) kinetics in continuous ambulatory peritoneal dialysis (CAPD) patients to establish therapeutic guidelines for two Cephalosporins commonly used to treat peritonitis in these patients. CFZ, 10 mg/kg, was given intravenously and intraperitoneally, while CPX, 500 mg, was given orally. CFZ led to serum concentrations of 25 μg/ml at 24 hr, with a half‐life (t½) of 33 hr. CAPD accounted for only 20% of total body clearance. When CFZ was given intraperitoneally, 74% of the dose was absorbed and similar serum concentrations had much the same t½. CPX, on the other hand, had a serum t½ of 8.6 hr and resulted in much lower peritoneal concentrations than CFZ. The kinetic principal of superposition provided a model for the prediction of plasma concentrations after repeated intraperitoneal doses of CFZ. The model predicts that a 10‐mg/kg intraperitoneal loading dose, followed by 5‐mg/kg doses in each exchange the first day and 2.5‐mg/kg doses thereafter, will lead to steady‐state plasma concentrations of 50 to 65 μg/ml. The data suggest that CFZ needs be given only intraperitoneally at doses lower than those in current use. CPX probably adds little to the treatment of peritonitis.

Short-term augmented calcium intake has no effect on sodium homeostasis.

To test the hypothesis that the supplementation of dietary calcium intake influences sodium homeostasis, the renin‐angiotensin system, and sympathetic nervous system in a manner that might evoke a decrease in arterial blood pressure, we gave 16 participants (eight normal and eight with hypertension) placebo for 8 days, followed by 500 mg elemental calcium as the carbonate salt twice a day for 8 days. The same diet was prepared for each meal for the entire study. Sodium intake was fixed for each participant and averaged 150 mEq/day. All urine was collected every day. Blood was drawn at the end of the placebo and calcium periods for determinations of plasma renin, aldosterone, and norepinephrine values. Calcium supplementation increased urinary calcium excretion significantly in both groups. However, calcium supplementation failed to influence sodium or potassium excretion, serum electrolytes, total serum calcium, renin, aldosterone, or norepinephrine levels, or heart rate. Systolic and diastolic blood pressures were not influenced in normal subjects, but in patients with hypertension the supine systolic blood pressure decreased significantly. We conclude that blood pressure lowering effects of calcium, should they occur, are not likely the result of augmented urinary sodium excretion or of straight‐forward influences on the renin‐angiotensin system or sympathetic nervous system.

The effect of piperacillin dose on elimination kinetics in renal impairment

SummaryThe effect of drug dose on piperacillin elimination kinetics was examined in 27 adult subjects with varying renal function. Piperacillin, 15 mg/kg or 60 mg/kg, was given by bolus intravenous injection. The elimination half-life (t1/2) increased five-fold and plasma clearance (Clp) decreased by 80% in patients with renal failure. Both parameters were dose dependent in patients with normal renal function, but not in patients with renal insufficiency. Piperacillin dose dependent elimination is due primarily to capacity limited renal excretion.

BIOAVAILABILITY AND KINETICS OF CIBENZOLINE IN PATIENTS WITH NORMAL AND IMPAIRED RENAL FUNCTION

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80‐mg intravenous infusion of 15N‐2‐cibenzoline and a single 80‐mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic—mass spectrometric assay. A compartment‐independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half‐life of 7.3 hours after the intravenous dose in healthy volunteers. In renal‐failure patients, cibenzoline clearance decreased to 224 mL/min and half‐life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal‐failure patients, respectively. Hemodialysis accounted for only 13% of drug clearance.