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To characterize the pharmacokinetics of gentamicin during and after hemodialysis (using polysulfone Fresenius F-80 membranes (Fresenius USA, Inc, Walnut Creek, CA), surface area 1.6 m(2)), eight patients with end-stage renal disease undergoing chronic hemodialysis receiving the drug for therapeutic indications were enrolled. Intradialytic gentamicin half-life, clearance, and amount of gentamicin recovered during a hemodialysis session were also determined. Serum gentamicin concentrations were analyzed using fluorescence polarization immunoassay. The amount of gentamicin recovered was 64.3 +/- 14.4 mg, whereas the intradialytic gentamicin half-life was 2.24 +/- 0.83 hours, with a clearance of 116 +/- 9 mL/min. Gentamicin concentrations rebounded by 27.86% +/- 16.4% at 1. 5 +/- 0.52 hours after the end of the hemodialysis session. The decrease in gentamicin concentrations comparing maximum rebound to prehemodialysis concentrations was 53.54% +/- 9.97%. A variable yet substantial amount of gentamicin is removed during hemodialysis using F-80 membranes; hence, supplemental doses are necessary to avoid potential treatment failures. The supplemental doses of gentamicin calculated based on gentamicin concentrations obtained immediately postdialysis could be overestimated if the postdialysis rebound concentrations are not considered. A dosing regimen is suggested using the pharmacokinetic parameters defined by the present study and population estimate of volume of distribution.

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To define the pharmacokinetics of vancomycin in patients undergoing maintenance hemodialysis in an acute care setting and to characterize the rebound phenomenon occurring after hemodialysis, vancomycin t1/2 during the interdialytic and intradialytic phases and intradialytic clearance were measured in eight critically ill patients undergoing high-flux hemodialysis using F-80 or F-60 polysulfone dialyzers. Intradialytic clearance was determined using the recovery method. In patients dialyzed with F-80 dialyzers, interdialytic and intradialytic t1/2 for vancomycin were 162 +/- 69.8 hours and 4.7 +/- 1.3 hours, respectively. Intradialytic clearance was 108.5 +/- 16.3 mL/min, and 238 +/- 55 mg of vancomycin was recovered in the dialysate. In patients dialyzed with F-60 dialyzers, interdialytic and intradialytic t1/2 were 211.0 +/- 166.8 and 4.6 +/- 0.4 hours, respectively. Intradialytic clearance was 100.6 +/- 18.3 mL/min and the amount of vancomycin recovered was 252 +/- 79 mg. Vancomycin concentrations rebounded by 16% to 37% between 3 and 6 hours in patients dialyzed with the F-80 dialyzer and 15% to 38% between 2 and 3 hours in patient dialyzed with F-60 dialyzers. Hemodialysis with high-flux polysulfone dialyzers removes significant amounts of vancomycin in patients dialyzed in an acute care setting. A suggested scheme for vancomycin dosage adjustments in these patients is presented.

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Limited information exists regarding the influence of dosage-release formulation on inhibition of drug metabolism. Therefore, the purpose of this study was to evaluate the effect of immediate-release (IR) and sustained-release (SR) verapamil on the pharmacokinetic parameters of propranolol in 12 healthy men. IR propranolol, 160 mg, was administered alone (Phase A) and following either IR verapamil, 80 mg t.i.d., (Phase B) or SR verapamil, 240 mg q.d., (Phase C) in a randomized crossover fashion. Of the 12 subjects enrolled, only seven were able to be analyzed secondary to assay interference. Oral clearances for L-propranolol for Phases A, B, and C were 198 +/- 70, 156 +/- 76, and 143 +/- 85 L/h, respectively. Oral clearances for D-propranolol for Phases A, B, and C were 203 +/- 96, 172 +/- 96, and 152 +/- 102 L/h, respectively. No significant differences were observed. However, when the verapamil groups (Phase B and C) were combined and compared to Phase A, a significant decrease in clearance for propranolol isomers was observed. In conclusion, due to the unexpected low numbers of patients evaluated, no significant differences in oral clearance were observed among the three treatment phases. However, there is a trend suggesting that SR verapamil had the greatest effect on propranolol clearance, which may warrant caution when changing from one formulation to another.

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OBJECTIVE: To report the unusual and poorly understood occurrence of vasopressor-resistant hypotension following a suicidal ingestion of theophylline. DESIGN: Single case report. SETTING: Eight-bed, respiratory intensive care unit in a 937-bed teaching hospital. PATIENT: A 52-year-old man with a past medical history significant only for hypertension. RESULTS: The additive influence of markedly elevated theophylline serum concentrations, status epilepticus, and vasopressor-resistant hypotension was associated with the patient's death. Intravenous dosages of epinephrine, norepinephrine, and phenylephrine (ranges 160-210, 32-105, and 200-250 micrograms/min, respectively) were ineffective in controlling the patient's dramatic hypotension. CONCLUSIONS: In addition to the usual metabolic abnormalities and central nervous system effects seen in theophylline poisoning, severe hypotension can occur and prove resistant to commonly used vasopressors. Early identification and treatment of theophylline poisoning is warranted to prevent the development of severe sequelae.

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Nine healthy male subjects received oral fluconazole 400 mg daily, ketoconazole 200 mg twice daily or no treatment for 6 days according to a randomized, cross-over design. A single 250 mg oral dose of phenytoin suspension was administered on day 5 and serum phenytoin concentrations were measured over the following 48 h. Serum testosterone concentrations were measured for 10 h after each dose of phenytoin. Ketoconazole had no significant effect on phenytoin concentrations while the mean AUC(0,48) for phenytoin was significantly higher with fluconazole (195.2 +/- 47.8 micrograms ml-1 h) than control (146.3 +/- 49.6 micrograms ml-1 h). At 48 h, the serum phenytoin concentration averaged 1.72 micrograms ml-1 under control conditions and 3.99 micrograms ml-1 with fluconazole (132% increase). AUC(0,10) for testosterone was 42% lower than control after ketoconazole administration (P less than 0.05) but increased by 33% from 55.6 +/- 9.4 ng ml-1 h (control) to 73.8 +/- 12.6 ng ml-1 h with fluconazole. AUC(0,10) values for the testosterone precursors androstenedione and 17 alpha-hydroxyprogesterone were significantly higher in the fluconazole treatment phase as were concentrations of luteinizing hormone. The mechanism and clinical significance of the increase in testosterone concentration caused by fluconazole remains to be determined.

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It is known that loss of renal function decreases the hepatic clearance of some drugs, but the mechanisms by which this occurs are unclear. Knowledge of which drugs display reduced hepatic metabolism may be important for appropriate dosing of these drugs in uremic patients. Although no firm conclusions can be made regarding common pharmacokinetic and metabolic characteristics of drugs that display decreased hepatic metabolism in renal failure, certain observations deserve consideration. It appears that drugs metabolized by oxidation, conjugation, or both may be predisposed to decreased hepatic clearance in renal failure. Drugs that undergo oxidation by the P-450IID6 isozyme may be more likely to exhibit inhibition whereas those metabolized by the P-450IIIA4 isozyme may be spared. Future studies designed to clarify the mechanisms of decreased hepatic clearance in renal failure should take into account the multiplicity of P-450 enzymes for drugs that are oxidatively metabolized. The phenomenon of reduced hepatic drug clearance in uremia should be considered when evaluating the influence of renal failure on drug disposition.

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