Pharmacokinetics and safety of multiple doses of daptomycin 6 mg/kg in noninfected adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis.

AIMS: The purpose of this study was to characterize the pharmacokinetics and tolerability of daptomycin in subjects undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). METHOD: 16 noninfected adults on stable dialysis regimens were enrolled. Daptomycin 6 mg/kg was administered after HD during a 48 h - 48 h - 72 h dialysis week or before a CAPD dwell time over a 48 h - 48 h - 48 h dialysis week. Pharmacokinetic parameters were described, and adverse events were monitored. RESULTS: Daptomycin had mean half-lives in HD subjects of 28.0 and 35.9 h on Days 1 and 5, with corresponding values of 25.8 and 26.7 h in CAPD subjects. Steady state was reached by Day 5 in both groups. At steady state, HD subjects had a mean peak plasma concentration (Cmax) of 81.6 µg/ml and a mean trough concentration of 15.3 µg/ml (on Day 8). In CAPD subjects, Cmax was 93.9 µg/ml and the trough was 20.7 µg/ml (on Day 7). Adverse events were experienced by 71.4% and 66.7% of HD and CAPD subjects, respectively. Most of these were mild or moderate in intensity; however, 2 subjects experienced muscle spasms and mild creatine phosphokinase elevations although neither event was considered to be related to study drug. CONCLUSIONS: The pharmacokinetics of daptomycin 6 mg/kg support a dosing regimen of every 48 h in CAPD and thrice-weekly dosing in HD.

Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment.

OBJECTIVE: The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator. METHODS: Thirty-two subjects aged > or = 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CL(CR)), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed. RESULTS: In subjects with CL(CR) 30 - 80 ml/min, the mean maximal telithromycin concentration at steady state (C(max),ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24 h) ss) was 33.4 mg x h/l. The mean C(max), ss and AUC(0-12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg x h/l, respectively. The increases in telithromycin C(max) ss and AUC(0-24 h) ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group deltaQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. CONCLUSIONS: The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.

The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function.

BACKGROUND: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG. METHODS: Subjects were stratified into five groups on the basis of iohexol clearance. After an overnight fast, all subjects received a single 1 gm dose of mycophenolate mofetil. Plasma concentrations of mycophenolic acid and MPAG were measured from 0 to 96 hours after administration. Mycophenolic acid and MPAG maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) for each group were determined from the mean plasma concentration-time profiles. Area under the plasma concentration-time curve values for mycophenolic acid and MPAG were calculated by the trapezoidal rule. The half-lives of mycophenolic acid and MPAG were calculated from the terminal portions of the concentration-time profiles. RESULTS: Mycophenolic acid clearance was not associated with changes in glomerular filtration rate (GFR). Cmax tended to increase as GFR declined. MPAG clearance correlated well with GFR (r2 = 0.905). Clearance of mycophenolic acid and MPAG were unaffected by hemodialysis. CONCLUSIONS: Clearance of mycophenolic acid after a single 1 gm oral dose of mycophenolate mofetil is unaffected by renal function. Clearance of mycophenolic acid is unaffected by hemodialysis. Diminished renal function should not require preemptive adjustment of 1 gm doses of mycophenolate mofetil; however dosage adjustment may be warranted on the basis of adverse effects or toxicity in individual patients. Mycophenolate mofetil can be administered irrespective of hemodialysis session without effect on mycophenolic acid exposure.

Diuretic strategies in patients with renal failure.

A thorough understanding of the clinical pharmacology of diuretic agents, particularly loop diuretics, is crucial in patients with abnormal (and those with normal) renal function. Renal insufficiency represents a pathophysiological state characterised by diuretic resistance. Diuretic resistance is defined as a diminished pharmacological response, or diminished natriuresis, to a given dose of a diuretic. The phenomenon of diuretic resistance is demonstrated by a shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response). Pharmacokinetic factors underlie the diuretic resistance observed in patients with renal failure. Diminished renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients' needs contribute to the diuretic-resistant state. In contrast, the pharmacological response of remnant (i.e. remaining) nephrons to diuretic agents remains intact. The time course of delivery of diuretics to their intraluminal site of action is an independent determinant of natriuretic response. An administration regimen that continuously maintains effective rates of excretion of diuretics into the urine would be expected to cause a greater overall natriuretic effect than the same amount of diuretic administered in intermittent doses. Thus, diuretic administration strategies that take account of the altered pharmacological responses in patients with renal failure are necessary to provide effective and safe treatment. Additionally, such strategies warrant revision by the prescribing physician as renal function changes over time.

Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency.

The safety of gadolinium (Gd-benzyloxypropionictetra-acetate [BOPTA] dimeglumine) infusion was evaluated in 32 patients with severe or moderate chronic renal failure in a prospective, randomized, double-blind, placebo-controlled study. Renal failure was defined as severe if creatinine clearance was between 10 and 29 mL/min, and as moderate if creatinine clearance was between 30 and 60 mL/min. Serum creatinine level and 24-hour urine samples for creatinine clearance were followed up serially for 7 days after the administration of either gadolinium (Gd-BOPTA dimeglumine), 0.2 mmol/kg, or a saline infusion. No patient experienced a significant change in renal function, defined as an increase in serum creatinine level greater than 0.5 mg/dL more than baseline, and no patient required hospitalization or dialysis during the study period. Gadolinium (Gd-BOPTA dimeglumine) appears to be well tolerated in patients with moderate to severe renal failure.

Aminoglycoside nephrotoxicity.

Aminoglycoside antibiotics maintain a leading role in antibacterial therapy of severe gram-negative infections despite nephrotoxicity complicating 10% to 20% of therapeutic courses. Risk factors for aminoglycoside-induced renal injury have been identified. A variety of maneuvers to protect renal function and minimize toxicity have been suggested, but few have been accepted for clinical use. Aminoglycosides are eliminated by glomerular filtration, but a fraction is reabsorbed in the proximal tubule. Polycationic aminoglycosides bind to anionic, brush-border, phospholipid membranes and are transported intracellularly. Disruption of normal phospholipid trafficking within the cell is evidenced by the presence of myeloid bodies, electron-dense concretions of phospholipid material. Although consistent with aminoglycoside injury, such biochemical and histological changes are observed with other drug exposures in which renal failure does not occur. Therapeutic drug monitoring services have failed to reduce aminoglycoside toxicity over the years, although two pharmacological parameters are imperative. The first is that peak aminoglycoside levels correlate with efficacy, as these agents display concentration-dependent bacterial killing. Second, trough levels reflect nephrotoxicity; the kidney is unable to excrete the dose of aminoglycoside within the dosing interval owing to impaired function. These two points have led to numerous reports evaluating once-daily dosing of aminoglycosides in which the cumulative dose for a 24-hour period would be administered as a single dose. This would take advantage of concentration-dependent "bug" killing as well as the post-antibiotic effect while minimizing repeated exposure and potential nephrotoxicity. Further trials are warranted to establish specific guidelines for once-daily as well as every 36- to 48-hour dosing regimens in patients with established renal impairment for specific organisms and specific types of infection.

Review article: the pharmacokinetics of rabeprazole in health and disease.

Rabeprazole, a newly developed proton pump inhibitor, has been shown to be effective for the treatment of gastric and duodenal ulcers and for gastro-oesophageal reflux disease. It is a rapid and potent inhibitor of gastric H+,K(+)-ATPase, the gastric acid (proton) pump. The maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) are linearly related to dose, while the time to maximum plasma concentration (tmax) and elimination half-life (t1/2) are dose-independent. Rabeprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system, and its metabolites are excreted primarily in the urine. Rabeprazole does not accumulate with repeated dosing. Its bioavailability is not influenced by the coingestion of either food or antacids. The pharmacokinetic profile of rabeprazole is substantially altered in the elderly and patients with stable compensated chronic cirrhosis; however, these alterations are not associated with clinically significant abnormalities in laboratory parameters or serious adverse events. The influence of severe decompensated liver disease on the pharmacokinetics of rabeprazole has not been assessed. The pharmacokinetic profile of rabeprazole is not significantly altered by renal dysfunction requiring maintenance haemodialysis. These findings suggest that dosage adjustment is not required in these special patient populations. Caution should be exercised, however, in patients with severe liver disease.

Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.

RATIONALE AND OBJECTIVES: To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS: The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1. RESULTS: Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+. CONCLUSIONS: Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

Isoprenoids and Ras: potential role in chronic rejection.

Protein prenylation, the post-translational attachment of isoprenoids to certain cellular proteins, increases protein hydrophobicity and promotes protein-membrane interactions. Of the many cellular proteins that undergo protein prenylation, particular attention has been paid to the protooncogene product Ras. Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" through which peptide growth factors such as PDGF, IGF-1, and FGF, and cytokines such as IL-2, IL-6, and GM-CSF stimulate intracellular events. Binding of these substances to their respective receptors on target cells can activate Ras, triggering intracellular signaling cascades which culminate in processes such as cell proliferation, differentiation, and T-cell activation. Protein prenylation inhibitors block Ras prenylation, prevent membrane localization of Ras, and inhibit growth and proliferation of a variety of cell types. Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection. Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats. Recipients treated with the HMG-CoA reductase inhibitor lovastatin, which inhibits isoprenoid production, showed significantly decreased allograft intimal area after 12 weeks, when compared with untreated recipients. In a separate study, recipients treated with the agent leflunomide, which inhibits growth factor receptor tyrosine kinases that can activate Ras, had significantly decreased allograft intimal area after 12 weeks. These results suggest that Ras may be important in chronic allograft rejection, and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection.

Rabeprazole: pharmacokinetics and tolerability in patients with stable, end-stage renal failure.

The authors compare the pharmacokinetic profiles, safety, and tolerability of rabeprazole, a new proton pump inhibitor (PPI), in healthy volunteers and in subjects with stable, end-stage renal failure. This single-center, open-label trial included two groups of subjects: 10 healthy males with 24-hour creatinine clearance > or = 90 mL/min/m2 and 10 males with renal failure (24-hour creatinine clearance < or = 5 mL/min/m2) receiving hemodialytic therapy. Normal subjects received a single, oral 20 mg rabeprazole dose. Those with renal failure received a 20 mg dose of rabeprazole on the day after hemodialysis and a second dose after a 2-week washout period during dialysis. Blood samples were drawn before and up to 24 hours after rabeprazole administration for determination of plasma rabeprazole concentrations by high-performance liquid chromatography. Safety and tolerability of rabeprazole were determined by reporting adverse events and comparing vital signs, ECG, physical examinations, and clinical laboratory tests before and during treatment. Comparison of pharmacokinetic results from healthy volunteers with those from subjects with renal failure indicated no clinically significant differences between groups. In addition, there were no statistically significant differences between any pharmacokinetic parameters recorded during or after hemodialysis. Rabeprazole was well tolerated by both groups. Only two drug-related adverse events were reported, and there were no significant treatment-emergent changes in vital signs or ECG. Treatment-emergent changes in hematologic and clinical chemistry parameters were observed for a few subjects in each group and generally represented only slight deviations from the normal range. These results indicate that no dosage adjustment of rabeprazole is required in patients with renal dysfunction. These findings and the well-documented clinical efficacy of this new PPI in patients with gastric ulcers, duodenal ulcers, or gastroesophageal reflux disease support rabeprazole's use in the treatment of patients with acid peptic disorders.

Pharmacokinetics of pilocarpine in subjects with varying degrees of renal function.

Data from three separate single-center studies were combined to assess the pharmacokinetics of orally administered pilocarpine. Pilocarpine concentration-time data were used to generate a data set including 42 subjects (34 males, 8 females) with varying degrees of renal function (average of two estimated creatinine clearance rates of 10 to 112 mL/min). Age ranged from 19 to 88 years. Subjects received single oral doses (range: 2.5-20 mg) of pilocarpine. Plasma samples were collected at time 0; at 20 and 40 minutes; and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours following dose administration. Cmax and AUC were normalized to a 5 mg exposure in those subjects who received doses other than 5 mg. Plasma pilocarpine concentrations were determined by gas chromatography/mass spectrometry. The pharmacokinetic parameters (elimination rate constant, Cmax, tmax, AUC, Vd/F, and Cl/F) in subjects with impaired renal function were similar to results found in other pharmacokinetic studies involving normal healthy volunteers with only Cmax being significantly higher (p < 0.05). No significant regression relationships were noted between creatinine clearance and pilocarpine elimination rate constant, tmax, Vd/F, Cl/F, or AUC. Pilocarpine clearance does not appear to be impaired in patients with varying degrees of renal insufficiency.

Disposition of recombinant human interleukin-10 in subjects with various degrees of renal function.

The pharmacokinetics of intravenously administered recombinant human interleukin-10 (rHuIL-10) were evaluated in 18 subjects with creatinine clearances (Clcr) between 2.7 and 116.7 mL/min/1.73 m2. Serum samples for rHuIL-10 were obtained over a 48-hour period after a single 25 micrograms/kg i.v. bolus infusion. AUC, total body clearance (Clp), and steady-state volume of distribution (Vdss) were derived by compartmental methods. Analysis of serum concentrations showed statistically significant group differences for log-transformed AUC and original scale Clp (p < 0.01). The AUC and effective half-life increased, while the mean Clp of rHuIL-10 decreased as renal function declined. A linear relationship between AUC and Clcr as well as Clp and Clcr demonstrates that the disposition of rHuIL-10 is altered in subjects with renal insufficiency. No serious adverse events were noted.

Mycotic endophthalmitis caused by Penicillium sp. after parenteral drug abuse.

A 30-year-old man developed endophthalmitis three weeks after an intravenous injection of hydromorphone hydrochloride. Penicillium species was recovered from a vitreous aspirate. Treatment with amphotericin B and flucytosine resulted in documented sterilization of the vitreous. At a six-month follow-up examination, the visual acuity of the involved eye was still limited to light perception.

The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.

STUDY OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction. DESIGN: Prospective, open-label study (studies 1 and 3); prospective, open-label, parallel-group study (study 2). SETTINGS: Two research centers and an inpatient clinic. SUBJECTS: Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance. INTERVENTION: Study 1, argatroban 125-microg/kg bolus followed by 4-hour continuous infusion of 2.5 microg/kg/minute; study 2, 4-hour infusion of 2.5 microg/kg/minute (1.25 microg/kg/minute in one patient with hepatic impairment); study 3, 5-microg/kg/minute continuous infusion over 4 hours. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two-compartment model with first-order elimination; effect response and plasma argatroban concentrations were well correlated. Mean +/- SD clearance, steady-state volume of distribution, and half-life values (40 healthy volunteers) were 4.7 +/- 1.1 ml/minute/kg, 179.5 +/- 33.0 ml/kg, and 46.2 +/- 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half-life of argatroban were increased approximately 2- to 3-fold; clearance was one-fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time. CONCLUSION: Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.

Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects.

STUDY OBJECTIVE: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies. DESIGN: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban. SETTING: University teaching hospital clinical research unit. PATIENTS: Healthy men (aged 22-62 yrs). INTERVENTION: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-microg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 microg/kg/minute with or without a 250-microg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-microg/kg bolus plus an infusion of 15, 20, 30, and 40 microg/kg/minute. MEASUREMENTS AND MAIN RESULTS: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 microg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated. CONCLUSION: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.

Zidovudine pharmacokinetics in five HIV seronegative patients undergoing continuous ambulatory peritoneal dialysis.

A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37-62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model-independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half-life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3-47.8 microns and area under the curve from 0.5-26.1 mg x hour/L. These differences resulted in corresponding differences in clearance (range 66-3176 ml/min/1.73 m2) and volume of distribution (range 16-825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.

Drug dosing guidelines in patients with renal failure.

The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient's glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.

Role of the sodium ion in acute renal failure.

Acute renal failure (ARF), an abrupt decline in renal function in its simplest terms, continues to elude precise pathophysiologic definition in human as well as experimental models. In the setting of ischemic or toxic renal injury, the role of sodium chloride as the major constituent of extracellular fluid volume (ECFV) is critically important in the maintenance of renal blood flow. Renal perfusion can be severely curtailed in states of ECFV depletion by activation of the renin-angiotensin axis leading to profound intrarenal hemodynamic alterations. This review will discuss evidence for the role of sodium chloride in the pathogenesis and modification of ischemic and toxic ARF. Much of the data arises from studies in experimental animal models of human disease. The results of clinical studies will be emphasized when available.

Determination of residual renal function with iohexol clearance in hemodialysis patients.

Residual renal function (RRF) may contribute significantly to the total dialysis prescription. Conventional quantitation of RRF in hemodialysis (HD) patients is measured by urea clearance and requires a 24-hour urine collection which is often difficult to perform and inaccurate. The renal clearance of iohexol was evaluated as an alternative method for RRF assessment (iohexol-derived RRF) in hemodialysis patients. An intravenous bolus of iohexol (12 ml; 300 mg iodine/ml) was administered to 42 hemodialysis patients following routine HD. A single blood sample was obtained approximately 44 hours later (pre-HD) to determine the plasma clearance of iohexol using x-ray fluorescence methods. Total body clearance of iohexol (CTBio) and non-renal clearance of iohexol (CNRio) 2.87 +/- 0.3 ml/min (mean +/SEM) were used to calculate iohexol-derived RRF (CTBio-CNRio). Iohexol-derived RRF determinations were then compared to urea clearance-derived RRF measurements. The RRF contribution to the dialysis prescription was also calculated utilizing iohexol-derived RRF compared to urea-derived RRF. Iohexol-derived RRF did not differ from urea-derived RRF (2.48 +/- 0.3 vs. 2.64 +/- 0.4 ml/min, P = 0.21). The RRF contribution to the weekly dialysis prescription (Kt/V) did not differ when iohexol-derived RRF was compared to urea-derived RRF (0.94 +/- 0.1 vs. 0.93 +/- 0.1, P = 0.9). Additionally, the effect of iohexol on RRF was assessed in 17 HD patients. Urea-derived RRF determinations one week after iohexol exposure did not differ from those measured one week prior to iohexol exposure (3.17 +/- 0.6 vs. 2.91 +/- 0.5 ml/min, respectively). Thus, renal clearance of iohexol can be an accurate and safe measure of RRF in HD patients and potentially simplify delivery of the dialysis prescription.