Pharmacokinetics of gabapentin in subjects with various degrees of renal function.

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

The effect of renal disease on the disposition of venlafaxine.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

Pharmacokinetics of lomefloxacin in renally compromised patients.

The single-dose pharmacokinetics of orally administered lomefloxacin (400 mg) were studied in normal subjects and in patients with various degrees of renal function. The subjects were classified by creatinine clearance (CLCR) normalized for body surface area: group 1, CLCR of greater than 80 ml/min/1.73 m2; group 2, CLCR of 80 to greater than 40 ml/min/1.73 m2; group 3, CLCR of 40 to greater than 10 ml/min/1.73 m2; and group 4, CLCR of less than or equal to 10 ml/min/1.73 m2. Each group consisted of eight subjects. The pharmacokinetics of lomefloxacin were significantly influenced by renal function. There were significant differences in the elimination rate constant, half-life, area under the concentration-time curve from 0 h to infinity, apparent total drug clearance, renal clearance, and apparent nonrenal drug clearance between the four renal function groups. Mean half-lives for groups 1, 2, 3, and 4 were 8.09, 9.11, 20.90, and 44.25 h, respectively. There were no significant differences between the renal groups for maximum concentration of the drug in serum and apparent volume of distribution. Age had no apparent effect on lomefloxacin disposition. There was a significant relationship between CLCR and lomefloxacin total body clearance (r = 0.92, P = 0.001) and renal clearance (r = 0.94, P = 0.001). Despite a predominate renal route of elimination, nonrenal lomefloxacin clearance significantly decreased with decreasing renal function (r = 0.72, P = 0.001). Mean lomefloxacin excretion rates over 48 h were 60.7, 56.0, 29.1, and 1.0% of the administered dose for groups 1, 2, 3, and 4, respectively. Mean glucuronide excretion rates over 48 h were 7.8, 6.3, 10.0, and 0.6% of the administered dose for groups 1, 2, 3, and 4, respectively. Hemodialysis had no effect on lomefloxacin concentrations in plasma. In patients with normal to moderate renal function, 400 mg of lomefloxacin per day should provide therapeutic concentrations in blood. The lomefloxacin dose should be reduced to 200 mg/day as the CL(CR) falls below 30 ml/min/1.73 m2. No additional dosage adjustments appear to be necessary for hemodialysis patients.

Inhibition of enoxacin absorption by antacids or ranitidine.

Ten normal volunteers participated in a randomized, five-way crossover study to determine the effect of concurrent enoxacin and antacid or ranitidine administration on enoxacin absorption. The bioavailability of a single oral 400-mg enoxacin dose was significantly decreased, by 73 and 49%, when Maalox TC was administered 0.5 and 2 h before enoxacin, respectively. Enoxacin bioavailability was not significantly altered when the antacid was given 8 h before or 2 h after enoxacin administration. Ranitidine, administered intravenously 2 h before enoxacin, also significantly decreased enoxacin bioavailability, by 40%. The correlation between the proximity of antacid administration and the magnitude of the decrease in enoxacin bioavailability supports complexation as the mechanism of the antacid-enoxacin interaction. However, reduction of enoxacin bioavailability by ranitidine suggests that elevated gastric pH may also play a role in the antacid-enoxacin drug-drug interaction.

Pharmacokinetics of cefoperazone (2.0 g) and sulbactam (1.0 g) coadministered to subjects with normal renal function, patients with decreased renal function, and patients with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered cefoperazone (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of renal failure. In an open, parallel experimental design, six normal subjects (creatinine clearance, greater than 90 ml/min), two patients with mild renal failure (creatinine clearance, 31 to 60 ml/min), eight patients with moderate renal failure (creatinine clearance, 7 to 30 ml/min), and four functionally anephric patients (creatinine clearance, less than 7 ml/min) were studied. The functionally anephric patients were given two test doses to allow study of drug disposition both on and off hemodialysis. Serial blood and urine samples were collected from time zero to 12 h after dosing in normal subjects and from 0 to 72 h in renal patients. Serum concentrations of both drugs declined biexponentially. For cefoperazone, the terminal elimination half-lives averaged from 1.6 to 3.0 h and were similar in subjects and patients. No cefoperazone pharmacokinetic parameters were appreciably altered by renal failure or hemodialysis, and there was no correlation between the total body clearance of cefoperazone and estimated creatinine clearance. In contrast, the sulbactam total body clearance was highly correlated with estimated creatinine clearance (r = 0.92, P less than 0.01) and was significantly higher in normal volunteers than in the renally impaired groups (P less than 0.01). The sulbactam terminal elimination half-life in functionally anephric patients (9.7 +/- 5.3 h) differed significantly from that of normal volunteers (1.0 +/- 0.2 h) and patients with mild renal failure (1.7 +/- 0.7 h, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of renal impairment and haemodialysis on single dose pharmacokinetics of oral enoxacin.

The effect of renal impairment on the single dose pharmacokinetics of oral enoxacin was studied in 28 volunteers with creatinine clearances ranging from less than 15 to 120 ml/min, including patients undergoing chronic haemodialysis. Following an overnight fast, 400 mg of enoxacin was administered orally to each subject. Blood and urine samples were collected at predetermined times for 48 and 72 h, respectively. Plasma and urine samples were assayed for enoxacin and for oxo metabolite concentrations by a specific high performance liquid chromatographic method. Area under the concentration-time curve from time 0 to infinity (AUC0-infinity) was increased in subjects with renal impairment. Plasma half-life (10.6-11.6 h) in volunteers with severe renal impairment was approximately double the 5.2 h half-life found in subjects with normal renal function, and this should result in steady-state enoxacin concentrations approximately double those measured in normal subjects given equivalent doses. Haemodialysis did not remove significant amounts of enoxacin. A significant correlation between creatinine clearance and enoxacin renal clearance was observed (r = 0.97).

Complexation versus hemodialysis to reduce elevated aminoglycoside serum concentrations.

Seven patients with acutely elevated aminoglycoside serum concentrations were studied comparing the effect of hemodialysis (n = 3) with removal by complexation using ticarcillin or carbenicillin (n = 4). Aminoglycoside serum half-life before intervention averaged 96 hours for the dialysis group and 67 hours for the complexation group. Ticarcillin was used for a minimum of 48 hours, while hemodialysis removal was estimated over 48 hours, which included two 4-hour dialysis periods. Aminoglycoside serum half-life was reduced to an average of 11 hours with hemodialysis, while with complexation using ticarcillin, it was reduced to 12 hours. During the 48-hour comparison period, complexation removed approximately 50% more aminoglycoside than did hemodialysis, primarily because the improved removal technique was sustained over the entire time. Complexation appears to be as effective as continuous hemodialysis in lowering excessive aminoglycoside serum concentrations. Complexation with ticarcillin can be more rapidly initiated, is less expensive and there is a low risk of adverse reactions. This method provides continued treatment of infections in patients with elevated serum concentrations and/or nephrotoxicity who require cessation of aminoglycoside therapy.

Pharmacokinetics of ceftazidime in patients with renal insufficiency.

The pharmacokinetics of ceftazidime were studied in 14 adult volunteers with different degrees of renal function. The elimination of ceftazidime was totally dependent on renal excretion. The clearance of ceftazidime ranged from 7.5 to 145.1 ml/min and correlated with both renal ceftazidime clearance and creatinine clearance (ClCR). It is recommended that 0.5 to 2.0 g of ceftazidime be given in extended dosages, with intervals dependent on the renal function of the patient. Patients with a ClCR of greater than 50 ml/min should be given ceftazidime every 8 h, those with a ClCR of 30 to 50 ml/min should be given the drug every 12 h, those with a ClCR of 15 to 30 ml/min should be given the drug once a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a 36- to 48-h regimen.

Massive hemorrhage from jejunal diverticula.

Three patients with bleeding jejunal diverticula that presented as life-threatening massive rectal hemorrhage were examined angiographically, with localization of the bleeding point. Vasopressin infusion did not result in adequate hemostasis in the two patients in whom it was attempted. Jejunal diverticula represent an uncommon, but not rare, source of massive gastrointestinal bleeding, usually presenting as "lower" tract hemorrhage. Without angiographic localization, surgical exploration for bleeding arising from jejunal diverticula has been difficult because of their occult nature and proximal location. A previously normal small intestine series does not preclude their presence.

Percutaneous drainage of pancreatic pseudocysts and abscesses.

The use of percutaneous drainage is reported in 6 patients with pancreatic pseudocysts and 6 patients with pancreatic abscesses. There have been no recurrences in the patients with pseudocysts. The success of the procedure is attributed to providing catheter drainage until the cavity was obliterated (mean time, 8 days), rather than using a single-needle aspiration. Percutaneous drainage of 6 pancreatic abscesses allowed desperately ill patients to improve enough to undergo elective surgery, and obviated surgery in 3 patients. The technique was performed without complications in all cases. Percutaneous drainage should find a significant place in the management of patients with complications of pancreatitis.

Percutaneous abscess drainage.

Forty-two abscess collections in the abdomen, pelvis and mediastinum were drained in 40 patients. Thirty-two were drained completely and required no operative treatment. The high success rate combined with the low morbidity rate and low mortality suggest that, if possible, percutaneous drainage of abscesses is preferable to operative drainage.

Mezlocillin disposition in chronic hemodialysis patients.

The pharmacokinetics of a single 1-g intravenous dose of mezlocillin were examined in six functionally anephric patients undergoing hemodialysis. Hemodialysis clearance calculated by plasma extraction ratios across the dialyzer membrane and by dialysis fluid agree well, averaging 26 and 32 ml/min. Dialyzer extraction ratios averaged 0.16 +/- 0.07, and 23.3 +/- 9.6% of the dose was measured in the dialysate. Plasma clearances (104 +/- 45 ml/min) and steady-state volumes of distribution (0.22 +/- 0.07 liter/kg) of mezlocillin showed good agreement with literature values. The nonrenal clearance (4.25 +/- 2.30 liters/h per 1.73 m2) of mezlocillin was appreciable. Drug loss by hemodialysis is small and should have little effect on therapeutic dosage needs.

Removal of cimetidine by peritoneal dialysis, hemodialysis, and charcoal hemoperfusion.

Dialysis clearance of cimetidine in patients receiving peritoneal dialysis, hemodialysis, and hemoperfusion was compared in stable and seriously ill patients. Two methods of determining dialysis clearance were employed, one of which was the method employed for cimetidine previously in the literature. Cimetidine clearance was lowest for peritoneal dialysis (5 ml/min), intermediate for hemodialysis (28 ml/min), and greatest for hemoperfusion (85 ml/min). Using both methods to calculate dialysis clearance, we found that cimetidine clearance during dialysis has been overestimated. In addition, pharmacokinetic analysis revealed that peritoneal and hemodialysis apparently removed cimetidine from the central compartment only, whereas hemoperfusion apparently removed drug from the peripheral compartment as well. A possible mechanism to explain this difference is based on the observation that hemodynamic changes occur during hemodialysis that may not be seen during hemoperfusion. No dosage adjustment need be made when patients receiving cimetidine undergo any form of dialysis; hemoperfusion may be of some benefit in removing drug from the central as well as tissue compartments in an acute overdose situation.