Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 microgram/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The alpha phase in these subjects had a mean half-life of 8.6 min while the half-life of the beta phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the gamma phase estimated from plasma data points between 12 and 24 hr averaged 1.2 +/- 3.6 hr. A terminal gamma t1/2 of 15.4 +/- 1.7 hr was calculated from 12-72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 8.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.

Six normal adult volunteers received

With the increasing use of artificial kidneys, numerous reports have appeared describing the pharmacokinetics of administered drugs in dialysis patients. Unfortunately, different investigators use different measures of dialysis clearance in reporting their results. Few studies have appeared in which actual measurements have been made in blood and dialysate as well as in plasma to experimentally show the variability of individual measurements and to demonstrate the inaccuracy of certain clearance measurements. We do so here, using the drug ethambutol. The effect of the artificial kidney on the removal of ethambutol was investigated in four uremic patients undergoing chronic hemadialysis. Ethambutol was administered by i.v. infusion over 30 min. Hemodialysis started at the end of drug infusion. Blood, plasma, and dialysate samples were collected periodically over 3 hr and analyzed for ethambutol content. Dialysis clearance was calculated by arterial-venous difference and by simultaneous dialysate measurement. The extraction efficiency of the hollow fiber dialyzers ranged from 36.2% to 43.8% in terms of blood and from 38.0% to 45.4% in terms of plasma. The mean clearance values due to dialysis were 108.08 and 88.1 ml/min measured with plasma and blood as body fluids of reference, respectively. Dialysis clearance calculated by dialysate measurement had a mean of 85.9 ml/min expressed as plasma and 74.7 ml/min expressed as blood. This study demonstrates that dialysis clearance when calculated using A-V difference and plasma flow is generally underestimated, particularly for a drug which extensively partitions into red blood cells. Ethambutol had a partition coefficient (blood/plasma) of greater than 1 in all four patients. The beta phase exhibited a mean half-life of approximately 2 hr on dialysis in comparison to off dialysis half-lives of 7 hr or longer in renal failure. Although ethambutol exhibits a markedly reduced half-life of the drug during hemodialysis, its recovery in the dialysis fluid during a 3-hr dialysis period constitutes only a small fraction of the dose administered.

No abstract

The hemodialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Cyclophosphamide 100 mg was given intravenously over 10 min before hemodialysis. Blood and dialysate samples were collected periodically during the 4 hr dialysis and measured by gas-liquid chromatography (GLC) for cyclophosphamide. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 ml/min, which is in the range of the metabolic clearance of 95 ml/min for the drug. The extraction efficiency of the hollow-fiber dialyzers averaged 40% for plasma and red blood cell (RBC) samples. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The half-life (t 1/2) of the beta phase was 3.3 hr in our patients during hemodialysis, a 49% reduction of the 6.5 hr to t 1/2 reported in uremic patients. Because of the reduction in elimination t 1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, we conclude that cyclophosphamide is dialyzable.