Ching S. Lee

Kinetics of oral ethambutol in the normal subject

Six normal adult volunteers received 15 mg/kg of ethambutol (EMB) by mouth, once as an aqueous solution and again as the commercial tablet preparation. Each dose was separated by at least 7 days. Plasma and urine samples were collected at regular intervals for up to 24 and 72 hr, respectively. Peak plasma concentrations ranged from 3.25 to 5.62 mcg/ml, 2 to 4 hr after tablet dosing. Earlier peak times were found after administering the solution. For plasma concentrations up to 12 hr there was a distinct distribution phase followed by an apparent elimination phase with a mean half‐life (t½) (±SD) of 4.06 ± 0.53 and 4.78 ± 0.41 hr for the tablet and the solution, respectively. Excretion rate plots exhibited similar t½values for the apparent elimination phase. An even longer tV2 of approximately 10 hr was evident from 24‐hr plasma samples and urinary excretion measurements up to 72 hr. Unchanged drug excreted in the urine averaged 61.1 ± 3.8 % of the dose for the tablet and 63.4 ± 2.6 % for the solution. Plasma protein binding for ethambutol determined by equilibrium dialysis and ultrafiltration was approximately 20% to 30%. The concentration ratio of ethambutol in erythrocytes to plasma ranged from 1.1 to 1.6.

Disposition kinetics of ethambutol in man

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 μg/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 α phase in these subjects had a mean half-life of 8.6 min while the half-life of the β phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the γ phase estimated from plasma data points between 12 and 24 hr averaged 11.2±3.6 hr. A terminal γt1/2 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 9.87 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.

Clearance calculations in hemodialysis: Application to blood, plasma, and dialysate measurements for ethambutol

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 hemodialysis. 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 arterialvenous 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 β phase exhibited a mean half-life of approximately 2 hr on dialysis in comparison to off dialysis half-lives of 7 hror 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.

Hemodialysis Clearance and Total Body Elimination of Carbamazepine during Chronic Hemodialysis

The effect of the artificial kidney on the removal of carbamazepine was studied in four uremic patients undergoing chronic hemodialysis. Each patient received 500 mg of carbamazepine PO 8 hr prior to hemodialysis. Predialysis and postdialysis blood samples as well as dialysate samples were collected at various time intervals during a 4-hr hemodialysis. Samples were analyzed for carbamazepine content by HPLC. Dialysis clearance calculated from dialysate measurements averaged 53.6 +/- 10.0 mL/min which is double the reported mean plasma clearance of 27.5 mL/min. Since drug clearance by the dialyzer is twice the endogenous plasma clearance, we conclude that carbamazepine is dialyzable. Despite the significant dialysis clearance, a dosage regimen adjustment may not be necessary because of the long elimination half-life of carbamazepine of 35 hr compared to the short length of the usual hemodialysis treatment of 3-5 hr.

Clearance and recovery calculations in hemodialysis: Application to plasma, red blood cell, and dialysate measurements for cyclophosphamide

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 (t½) of the beta phase was 3.3 hr in our patients during hemodialysis, a 49% reduction of the 6.5 hr t½ reported in uremic patients. Because of the reduction in elimination t½, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, we conclude that cyclophosphamide is dialyzable.

Hemodialysis of Theophylline in Uremic Patients

Hemodialysis of theophylline was studied in three uremic patients. The dialysis clearance ranged from 75.6 to 97.9 ml/min and averaged 88.1 ml/min. A much smaller value of 32.8 ml/min was reported by Levy and associates. The difference may be attributed to the two monitoring factors during hemodialysis, namely, blood and dialyzate flow rates. Both were higher in our study. Analysis of the semilogarithmic plots of the arterial plasma concentration versus time over a 3-hour period gave apparent half-lives of 3.15, 2.04, and 2.73 hours, respectively, for the three patients. Half-life of theophylline in normal subjects ranged from 4 to 6 hours or even longer. A prolonged half-life of theophylline in uremia could be expected. Our kinetic study indicated an approximately 50 per cent reduction in terminal half-life during hemodialysis. Hourly dialyzate was collected from one patient to account for drug recovery in the dialysis fluid. Forty per cent of the administered dose was recovered in the dialyzate during a 3-hour dialysis period, indicating effective removal. Dialysis clearance for creatinine was calculated by arterial-venous difference and correlated with that of theophylline. We found that theophylline was cleared by the dialyzer at a rate approximating 63 per cent of creatinine removal.

Hemodialysis for Acetaminophen Detoxification

AbstractThe effect of an artificial kidney on the removal of acetaminophen and its metabolites (glucuronide and sulfate) was investigated in six chronic hemodialysis patients. Acetaminophen 650 mg was given orally 2 h prior to hemodialysis. Plasma and dialysate samples were collected periodically over 3 h and analyzed by hplc for acetaminophen content. Dialysis clearance was calculated by arterial-venous difference and simultaneous dialysate measurement. The extraction efficiency of the hollow-fiber dialyzers averaged 47.5 and 43% for the parent compound and the total metabolites, respectively. The mean dialysis clearance of 112 mL/min for acetaminophen measured with blood as the body fluid of reference was confirmed by calculation of clearance using dialysate measurement. A comparable dialysis clearance value of 105.8 mL/min was obtained for the total metabolites. A mean of 70.5 mg of acetaminophen of 11% of the administered dose was removed during the 3-h dialysis period. However, the total metabolites ...

Acetaminophen-diphenhydramine interaction in rabbits

Acetaminophen-diphenhydramine interaction was investigated by oral administration of acetaminophen to rabbits, alone or in combination with diphenhydramine. Blood samples were collected before and 0.25. 0.5, 0.75, 1.0, 2.0, 3.0, 4.0, 5, 0 and 6.0 h after acetaminophen administration. Assays of acetaminophen in plasma samples were carried out using a HPLC method. Diphenhydramine significantly reduced the maximum plasma concentration (Cmax) of acetaminophen. Diphenhydramine, however, had little effect on the time taken to reach the maximum plasma concentration (Tmax), the area under the plasma concentration-time curve (AUC∞0) and the elimination half-life (t12) of acetaminophen. Gastric emptying experiment was performed by injecting into the rabbit stomach phenol-red containing solution with and without diphenhydramine. The gastric content recovered at 0.5 h was analyzed for phenol-red remaining to determine the rate of gastric emptying. Diphenhydramine significantly increased the weight percentage of phenol-red remaining in the rabbit stomach 0.5 h post-injection. It was concluded that diphenhydramine affected the rate but not the extent of acetaminophen absorption by delaying the gastric emptying.

Effects of chlorpromazine and atropine on acetaminophen absorption in rabbits

The effects of chlorpromazine and atropine on the gastrointestinal absorption of acetaminophen were investigated in rabbits. Two doses of chlorpromazine and atropine were injected intraperitoneally 30 min prior to the oral administration of acetaminophen. Blood samples were collected before and 0.25,0.5,0.75, 1.0,1.5,2,3,4,5 and 6 h after acetaminophen administration and were analyzed for acetaminophen contents using a HPLC method. Chlorpromazine at a 10 mg/kg dose significantly reduced the maximum plasma concentration (Cmax) of acetaminophen from 64.2 ± 2.8 to 40.0 ± 6.3 μgg/ml(P < 0.05). In addition, chlorpromazine at 5 and 10 mg/kg doses significantly increased the time taken to reach the maximum plasma concentration (Tmax) of acetaminophen from 0.29 ± 0.04 to 0.67 ± 0.15 and 0.96 ± 0.21h, respectively (P < 0.05). Atropine at 0.5 and 1.0 mg/kg doses also significantly reduced the Cmax of acetaminophen from 69.6 ± 4.7 to 45.6 ± 3.7 and 45.9 ± 6.7 μg/ml, respectively (P < 0.05). However, atropine has little effect on Tmax of acetaminophen. Both chlorpromazine and atropine did not seem to affect the area under the plasma concentration-time curve and the elimination half-life of acetaminophen. It was concluded that chlorpromazine and atropine affect the rate but not the extent of acetaminophen absorption, by delaying the gastric emptying.