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The kinetics of oral ketoconazole in serum and peritoneal fluid were studied in six patients with renal failure receiving peritoneal dialysis. A dose of 400 mg ketoconazole resulted in a maximum blood concentration of 2.3 +/- 1.7 microgram/ml (mean +/- SD), which occurred 3.3 +/- 1.6 hours after dosing. The serum t1/2 was 2.4 +/- 0.8 hours. Peritoneal clearance values were less than 1 ml/min, and peritoneal penetration reached 3.4% of the serum concentration by 5 hours. Protein binding studies were also performed. Compared with healthy controls, patients receiving peritoneal dialysis have significantly less ketoconazole serum protein binding. Fifty to eighty percent of the drug is protein bound in the peritoneal fluid, and the unbound concentration is in the same range as that in the serum of healthy individuals with "therapeutic" total ketoconazole levels of 1 to 2 micrograms/ml.

Kinetic parameters and bioavailability of cefadroxil were studied in 20 subjects with differing renal function as measured by endogenous creatinine clearance (CCr). Two subjects were on hemodialysis. After an overnight fast, each subject ingested two 500-mg capsules of cefadroxil. The peak serum concentration was variable (12 to 57 mg/L) and correlated inversely with the CCr. All but one patient had maximum absorption within 4 hr of ingestion and in most patients the peak was reached within the 2-hr sample. Urinary recovery within 48 hr was 45% to 106% when CCr greater than 8 ml/min. Even in patients with the most severe renal failure (CCr less than 10 ml/min), urine concentrations of cefadroxil were adequate to treat susceptible bacteria. The rate of oral absorption ka, was not affected by the state of renal function and was 0.76 +/- 0.50 hr-1. The apparent distribution volume (V d ext) was 0.28 +/- 0.09 L/kg. The plasma elimination rate was dependent on CCr wih a small fraction of drug being removed by nonrenal routes. Except in advanced renal failure, tubular secretion was present since renal clearance of cefadroxil exceeded CCr. The data suggest that little drug accumulation will occur with the usual 8- to 12-hr dosing schedule except when the CCr is less than 25 ml/min.

Eighty-two hospitalized adult patients were randomized to treatment with gentamicin or tobramycin. Serum levels were compared to computer-derived mathematically predicted levels to evaluate predictability of gentamicin and tobramycin serum levels. When comparable dosages were used mean peak gentamicin levels (4.87 micrograms/ml) did not differ from those after tobramycin (4.31 micrograms/ml). Seventy-three percent of patients had peak levels after gentamicin greater than 4.0 micrograms/ml compared to 46% after tobramycin. Factors purported to influence predictability of aminoglycoside serum levels were examined. In 46 of 74 patients whose actual body weight was 10 to 35 kg less than estimated ideal body weight levels after both drugs were lower than predicted. Serum levels were also lower than predicted in 7 of 11 patients with ascites, 6 of 7 patients receiving carbenicillin therapy, and 17 of 29 patients who had pneumonia. Neither hematocrit nor temperature appeared to influence predictability of serum levels. A comparison of methods used to obtain computer-derived predicted levels showed that ideal body weight provided the most accurate prediction. Differences between predicted and measured levels were established when calculations were based on actual body weight (P = 0.009) or on surface area (P = 0.003 for peak and 0.023 for trough levels).

Furosemide kinetics were studied in 4 normal subjects after single intravenous injections (1 mg/kg). One experiment was done after pretreatment with probenecid. The apparent volume of furosemide distribution was unchanged after probenecid (10.9 L). The mean plasma clearance fell from 155 to 85 ml/min and the mean plasma t1/2 rose from 36 to 61 min. Renal clearance of furosemide fell below 50% of control after probenecid, but the kidney remained the main route of its excretion (75% of the dose appeared in the urine). In another experiment in 4 subjects an infusion of furosemide was sustained following a loading dose to maintain a constant plasma level. After a control period, probenecid was given orally. This resulted in a decrease in renal excretion of furosemide with a simultaneous rise in its plasma concentration. Despite the rising plasma furosemide concentration, however, there was a diminution in both urine flow and the excreted fraction of filtered sodium, which suggested some reduction of diuretic action. In doses commonly used, probenecid reduces renal elimination of furosemide in man with only a mild impairment of its diuretic activity. This suggests that furosemide is eliminated predominantly by way of proximal tubular secretion and that tubular rather than plasma concentration is the main determinant of its diuretic effect.

Cefonicid is a cephalosporin with a longer t1/2 than currently available cephalosporins. Cefonicid kinetics after an intravenous dose of 7.5 mg/kg were followed in four groups of subjects: group 1, four subjects with normal creatinine clearance (Clcr greater than 80 ml/min); group II, seven subjects with mild renal insufficiency (Clcr 50 to 80 ml/min); group III, five subjects with moderate to severe renal impairment (Clcr 8 to 49 ml/min); and group IV, five subjects with end-stage renal disease who were receiving maintenance hemodialysis (Clcr less than 8 ml/ml). Cefonicid volume of distribution ranged from 6.9% to 17.6% body weight but was not related to Clcr. Elimination t1/2 was 4.6 +/- 0.7 hr in group 1,6.0 +/- 2.7 hr in group II, 25.6 +/- 14.0 hr in group III, and 65.3 +/- 43.6 hr in group IV. There was a strong correlation between plasma cefonicid clearance and Clcr. Nonrenal clearance did not change with decreasing Clcr. Hemodialysis clearance calculated from plasma concentrations and recovery in dialysate was 2.5 +/- 0.9 ml/min. These kinetic parameters were used to formulate dosage regimens for patients with renal impairment.

Kinetics of sotalol, a beta adrenoceptor blocker, was studied in 20 patients with varying renal function. In subjects with creatinine clearance (Clcr) greater than or equal to 39 ml/min/m2, sotalol plasma clearance (x +/- SD) was 71 +/- 31 ml/min/m2, elimination half-life (t 1/2) was 8.1 +/- 3.4 hr, and renal clearance was 46 +/- 26 ml/min/m2. In patients with moderate renal impairment (Clcr = 8 to 38 ml/min/m2) elimination t 1/2 rose to 24.2 +/- 7.5 hr, and plasma clearance fell to 24 +/- 7 ml/min/m2. In patients receiving dialysis, elimination t 1/2 rose to 33.9 +/- 27.1 hr. Elimination t 1/2 during hemodialysis was 5.8 +/- 2.1 hr and was associated with a 56.7 +/- 21% reduction in plasma levels.

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half-lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half-lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half-life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end-stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half-life in patients with ESRD needs further study to evaluate possible dose-dependent kinetics.