Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients.

OBJECTIVES: To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved. METHODS: The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extended-release tablet with 250 mL commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit or water in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) was determined. Furanocoumarin and naringenin precursor (naringin) concentrations were measured in each grapefruit treatment. RESULTS: Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than that with water. Felodipine peak concentration was higher, but the half-life was unchanged. The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumarins produced mechanism-based and competitive inhibition of CYP3A4. Bergamottin was the most potent mechanism-based inhibitor. Naringenin isomers produced only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, and naringin concentrations varied among grapefruit treatments but were sufficient to inhibit markedly in vitro CYP3A4 activity. CONCLUSIONS: Unprocessed grapefruit can cause a drug interaction with felodipine. The active ingredients are naturally occurring in the grapefruit. Bergamottin is likely important in drug interactions with commercial grapefruit juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.

EEG and clinical associations with mortality in comatose patients in a general intensive care unit.

The authors examined EEG findings and clinical factors for their association with outcome in comatose patients in their general intensive care unit. The following individual and combinations of factors were strongly related to mortality, with positive predictive values of >0.80 and odds ratios >2.0: age over 65 years, anoxic/ischemic encephalopathy, EEG suppression, lack of EEG reactivity; anoxia-ischemia with partial or complete cranial nerve areflexia, anoxia-ischemia with EEG suppression; anoxia-ischemia and generalized epileptiform activity; anoxia-ischemia with partial cranial nerve areflexia and EEG suppression. Conversely, the following factors favored survival rather than death: systemic infection/sepsis, metabolic derangement (excluding anoxic-ischemic insult), trauma; dysrhythmia, focal epileptiform activity, and regional delta and reactivity on EEGs. The findings of this study support the integration of these data into intensive care unit prognostic scoring systems, such as later versions of the Acute Physiology and Chronic Health Evaluation (APACHE).

Grapefruit juice-felodipine interaction: effect of naringin and 6',7'-dihydroxybergamottin in humans.

OBJECTIVE: To test whether naringin or 6',7'-dihydroxybergamottin is a major active substance in grapefruit juice-felodipine interaction in humans. METHODS: Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6',7'-dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study. RESULTS: The amounts of naringin and 6',7'-dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of felodipine were higher with supernatant fraction (81 nmol.h/L and 20 nmol/L), particulate fraction (117 nmol.h/L and 24 nmol/L), and grapefruit juice (130 nmol.h/L and 33 nmol/L) compared with water (53 nmol.h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for felodipine and a similar Cmax of felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydrofelodipine nor decreased the AUC ratio of dehydrofelodipine to felodipine compared with water. Individually the supernatant fraction consistently produced lower felodipine AUC and Cmax compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction. CONCLUSIONS: Naringin and 6',7'-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice-felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsible for inhibition of cytochrome P450 3A4 in humans.

An electroencephalographic classification for coma.

BACKGROUND: The assessment of thalamocortical function in comatose patients in the intensive care unit (ICU) can be difficult to determine. Since the electroencephalogram (EEG) affords such assessment, we have developed an EEG classification for comatose patients in our general ICU. METHODS: One hundred EEGs were classified in a blinded fashion by two EEGers, using our method and that of Synek. Interobserver agreement was assessed using kappa score determination. RESULTS: Kappa scores were 0.90 for our system and 0.75 for the Synek system. (The Kappa score represents the inter-rater agreement that is beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial agreement). CONCLUSION: Our system for classifying EEGs in comatose patients has a higher interobserver reliability than one that was previously published. This EEG classification scheme should be useful in clinical electrophysiological research involving ICU patients, allowing for internal consistency and comparisons among centres.

Computed tomography evaluation of patients with chronic headache.

OBJECTIVE: To determine whether the rate of detecting a tumour, arteriovenous malformation (AVM) or aneurysm with the use of enhanced or unenhanced computed tomography (CT) is significant in patients with chronic headache and to calculate the cost. DESIGN: Case series. SETTING: Chronic headache clinic at a tertiary care referral centre. PATIENTS: All 373 consecutive patients with chronic headache (284 women, 89 men) referred for CT scanning from May 1987 to October 1992 who met one or more of the following criteria: increased severity of symptoms or resistance to appropriate drug therapy (287 patients [76.9%]), change in characteristics or pattern of headache (78 [20.9%]) or family history of intracranial structural lesion (8 [2.1%]). INTERVENTIONS: CT scans of the head were enhanced with nonionic contrast medium (292 scans), were unenhanced (70) or involved both methods (40). OUTCOME MEASURES: Number and nature of minor and major findings, and total price per scan. RESULTS: Of the 402 CT scans 14 (95% confidence interval [CI] 7 to 21) revealed minor findings that did not alter patient management: infarct (9 scans), cerebral atrophy (2), cavum vergae (1), hyperostosis frontalis interna (1) and communicating hydrocephalus (1). Four scans (95% CI 0 to 8) showed significant lesions: osteoma (2), low-grade glioma (1) and aneurysm (1); only the aneurysm was treated. There were no cases of AVM. An unenhanced scan cost $82.63 and an enhanced scan $204.05. The cost per significant finding was over $18,000. In all, it cost $74,243 to find one treatable vascular lesion. CONCLUSIONS: The detection rate of CT scanning in patients with chronic headache is similar to that expected in the general population, provided the neurologic findings are normal. The cost of detecting intracranial lesions in this patient population is high [corrected].

Ataxia in institutionalized patients with epilepsy.

Fifty-four per cent of 41 chronically institutionalized adult patients with epilepsy had ataxia of gait (wide mean stride width). None of the following correlated with stride width: serum phenytoin, previous phenytoin toxicity, seizure frequency, or status epilepticus. Seventeen of the 41 patients had computed tomographic head scans. Patients with radiological evidence of cerebellar atrophy had a wider mean stride width, later age of onset of seizures, greater peak serum concentrations of phenytoin than did those without cerebellar atrophy. Ataxia of gait was inconsistently associated with cerebellar atrophy. Elevated serum/plasma concentrations of phenytoin may be a risk factor for cerebellar atrophy, but seizure frequency or status epilepticus are not independently related to this complication.

Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain.

To compare the safety and efficacy of subcutaneous and intravenous infusion of opioid analgesics, a randomised, double-blind, crossover trial was carried out in inpatients. 15 patients with severe cancer pain received two 48 h infusions of hydromorphone--one subcutaneously and one intravenously in randomly allocated order. The study was made double-blind by the use of two infusion pumps throughout; during the active subcutaneous infusion the intravenous pump delivered saline and vice versa. Serial measurements of pain intensity, pain relief, mood, and sedation by means of visual analogue scales showed no clinically or statistically significant difference between the two infusion routes. Side-effects were slight, and the mean number of morphine injections for breakthrough pain did not differ significantly between the routes (4.8 [SD 4.5] for intravenous vs 5.3 [5.6] for subcutaneous). Plasma hydromorphone concentrations measured at 24 h and 48 h of infusion showed stable steady-state pharmacokinetics; the mean bioavailability from subcutaneous infusion was 78% of that with intravenous infusion. Because of the simplicity, technical advantages, and cost-effectiveness of continuous subcutaneous opioid infusion into the chest wall or trunk, intravenous opioid infusion for the management of severe cancer pain should be abandoned.

A comparative analysis of two dosing strategies of flurbiprofen in rheumatoid arthritis: an application of sequential trial design.

Forty patients with classic or definite rheumatoid arthritis were entered into a double-blind, randomized, multiple crossover, sequential trial comparing two doses (300 mg vs 150 mg per day) and two dosing schedules (b.i.d. vs t.i.d.) of flurbiprofen. Clinical assessments (Ritchie Index, grip strength, walking time, physician and patient global assessments) were made at baseline and at biweekly intervals during the next six weeks of active treatment. Overall there were no statistically significant differences either between the two dosage levels or the dosing schedules. This study demonstrates the utility of the sequential trial design in assessing drug efficacy. The data confirm a lack of difference between the two doses of flurbiprofen selected and suggest that twice-daily dosing with flurbiprofen is similar in efficacy to thrice-daily dosing.

Midazolam: kinetics and effects on memory, sensorium, and haemodynamics.

This study aimed not only to compare the pharmacokinetics of oral and intravenous doses of the new water-soluble benzodiazepine, midazolam, but also to study the effects on haemodynamics, sensorium, and memory performance. Eight normal human volunteers each received a single 15 mg dose of midazolam base orally and intravenously in randomized sequence 2 weeks apart. Serial venous samples were obtained for 12 h after dosing. Vital signs, sensorium testing and memory testing using word lists were also performed. Computerized non-linear least squares curve-fitting of the two-compartment open model to the oral and intravenous data simultaneously yielded the following estimates: V1, 0.33 1 kg-1, VdSS, 1.08 1 kg-1, t1/2,lambda, 0.10 h, t1/2,Z, 1.89 h, ka 1.17 h-1 and bioavailability, 49%. The intravenous dose decreased the systolic pressure 22 mm Hg during the first half-hour and the oral dose had 50% less effect. Most subjects became drowsy halfway through the infusion and were only rousable to voice by its end. The sensorium was clear by 2-3 h. After oral dosing the peak sensorium effects of ataxia-dysarthria were seen at 30 min and had cleared by 2 h. Memory testing showed that memory acquisition was markedly impaired for at least 90 min after the intravenous dose and slight recovery was apparent at this time after the oral dose. Memory performance was proportionately more impaired than the sensorium score. We conclude that: midazolam kinetics are characterized by rapid absorption, but incomplete bioavailability and rapid elimination, midazolam intravenously may lower blood pressure significantly, and the level of consciousness correlates poorly with the degree of memory impairment.

Efficient pharmacokinetic modeling of complex clinical dosing regimens: the universal elementary dosing regimen and computer algorithm EDFAST.

Dosing regimens used in clinical practice are often complex, involving several different routes of administration, dose sizes, dosing rates, and dosing intervals and durations. A novel universal elementary dosing regimen (uedr), that allows general pharmacokinetic modeling of these clinical regimens, is presented and developed mathematically. The uedr concept is computationally efficient, mathematically exact, and logically simple, and can replace the disparate standard concepts and equations of elementary infusion, "bolus" injection, multiple injection, oral dosing, zero-order-release dosing, etc. An optimized computer algorithm (EDFAST) based on the uedr approach, that readily permits the creation of a single fast and versatile microcomputer program for the analysis of all complex dosing regimens in any set of linear compartmental models, is presented. This is of particular relevance to three areas of application in clinical pharmacokinetics: compartmental drug concentration or amount versus time course prediction (simulation) with known model parameter values; parameter estimation (curve-fitting) from measured concentration versus time data; and individualized complex dosing regimen calculation (optimization) for target sets of concentration-time points. Application examples that show the versatility of the uedr approach are presented in detail.

Lidocaine therapy with an exponentially declining infusion. Clinical evaluation of an optimized dosing technique.

A novel technique to achieve rapidly and continually maintain therapeutic lidocaine concentrations was designed according to known pharmacokinetic properties of the drug and was tested in 12 patients who required immediate lidocaine prophylaxis because of suspected acute myocardial infarction. The serum lidocaine concentrations achieved by this method remained within the therapeutic range (1.2 to 5.0 mg/L) in 83 of 84 determinations and showed little fluctuation over time for individual patients. Unlike previously recommended dose regimens for lidocaine, this technique uses an exponentially declining infusion and has the advantages of greater simplicity, less chance of medication error, and avoidance of rapid changes of lidocaine concentrations. Furthermore, similar methods can be applied when rapid attainment of stable plasma drug concentrations is needed for clinical or experimental pharmacologic studies.

Comparative trial of indapamide and hydrochlorothiazide in essential hypertension, with forearm plethysmography.

Seventeen patients (11 males) 34-66 years in age with uncomplicated essential hypertension completed a randomized, placebo-controlled, double-blind cross-over study comparing indapamide (IND) 2.5 mg q am with hydrochlorothiazide (HCT) 50 mg q am. The lead-in placebo period of 2 months was followed by two active drug phases of 3 months' duration separated by a 2-month placebo-washout period. The mean standing systolic/diastolic pressures (+/- SD) during placebo were 150 +/- 18/98 +/- 6 mm Hg. The pressures were 137 +/- 16/90 +/- 7 IND and 137 +/- 17/91 +/- 7 mm Hg on HCT. Thus the drugs produced similar systolic, diastolic, and mean arterial pressures. Orthostatic changes in mean pressure and heart rate were similar with the two drugs. Both drugs decreased serum potassium (-14.3% with IND and -13.7% with HCT), and increased serum uric acid (+26.7% with IND and +25.7% with HCT), and cholesterol (+11.7% with IND and +11.1% with HCT) equally. Forearm blood flow (FBF) and venous compliance (FVC) were measured by a plethysmographic technique in six of the patients. FBF during placebo of 3.53 +/- 0.58 ml/min/100 ml forearm volume was increased to 4.01 +/- 0.74 ml/min during IND and decreased to 3.40 +/- 1.16 ml/min on HCT, but our sample size did not permit detection of significant differences. FVC was not altered from baseline by the drugs. No side effects attributable to either of the two drugs were elicited. We conclude that IND did not differ from HCT in its effect on blood pressure, heart rate, venous compliance, or biochemistry. A possible peripheral arteriolar vasodilator effect on IND should be investigated further.

Kinetic disposition of intravenous ceftriaxone in normal subjects and patients with renal failure on hemodialysis or peritoneal dialysis.

The kinetic disposition of a single intravenous dose of ceftriaxone (250 to 665 mg) was studied in six normal subjects and nine patients with renal insufficiency and normal hepatic function. In normal subjects, ceftriaxone was eliminated with a t1/2 beta of 5.2 h (range, 4.1 to 5.8). The total body clearance (Qb) was 13.5 ml/kg per h (range, 8.4 to 23.3), and renal clearance was 8.3 ml/kg per h (range, 5.8 to 13.3). In patients with severe renal insufficiency requiring peritoneal or hemodialysis, the mean t1/2 beta was prolonged to 13.4 h (range, 7.7 to 15.8) and the mean Qb was reduced to 6.9 ml/kg per h (range, 3.4 to 12.8). The apparent volumes of distribution (Vc and Vss) were not different from those determined in normal subjects. Peritoneal dialysis did not remove ceftriaxone. The dialysate of three patients on continuous peritoneal dialysis did not contain any measureable ceftriaxone, and the kinetic disposition in these patients was similar to the hemodialysis patients between their dialysis treatment. During a 4-h hemodialysis session, the total body clearance of ceftriaxone was reduced, perhaps secondary to a decrease in hepatic blood flow induced by the hemodialysis procedure. After a 12- or 24-h dose regimen, predicted trough concentrations of ceftriaxone in plasma at steady state derived from kinetic data generated from the study and assuming linear pharmacokinetic behavior were well above the minimum inhibitory concentrations of most sensitive bacteria, suggesting the feasibility of a once-a-day dosage regimen especially for patients with severe renal insufficiency.

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.

Metronidazole kinetics in dialysis patients.

Five volunteers with normal renal function (NOR) and eight patients with renal insufficiency (REN) were given a single dose of 500 mg metronidazole (MET) intravenously over 26 minutes. Serial venous plasma samples were taken at certain intervals for 30 hours. Four of the eight REN patients were also given the drug at the start of hemodialysis and four simultaneous inflow-outflow samples were taken over 4 hours of dialysis. Plasma MET, the acetic acid metabolite (MTAC), and the hydroxymethyl metabolite (MTOH) were determined by high-pressure liquid chromatography assay. Plasma MET over time curves were analyzed with a nonlinear curve-fitting computer program (ASAAM-27) which employed a two-compartment open model. Plasma MET concentrations were similar in the NOR and REN groups. The volumes of distribution for MET--both V1 and Vdss--were similar in the two groups. Moreover, renal insufficiency did not affect the beta half-life (6.5 hours) or the plasma clearance (10.1 L/hr) of MET. Metabolite concentrations peaked at about 12 hours in both groups, but peak MTAC was five times higher in the REN group and peak MTOH twofold higher. Plasma clearance of MET by dialysis averaged 4.0 L/hr at 30 minutes, but thereafter ranged from 2.9 to 4.2 L/hr. Clearance of MTAC ranged from 5.8 to 7.8 L/hr and that of MTOH 2.7 to 5.6 L/hr. We concluded that renal failure does not alter MET disposition but is associated with significant accumulation of the metabolites of MET, possibly requiring a dose reduction. Moreover, an 8-hour hemodialysis eliminates approximately 50% of an administered dose of MET.

Biologic activity of metronidazole in plasma and urine of volunteers with normal or impaired renal function.

In this study, we have compared a bioassay procedure with high-pressure liquid chromatography (HPLC) for the determination of metronidazole levels in serum and urine. Plasma and urine of volunteers with normal or impaired renal function were obtained at various intervals after a single intravenous dose of 500 mg metronidazole. In plasma of normal volunteers 30 hours after dosing, the bioassay gave results comparable to the total values of the parent compound plus metabolites. In patients with renal failure, the course of the plasma regression curve of metronidazole as measured by the bioassay procedure was intermediate between the values of metronidazole alone and the total values of parent compound plus metabolites. Recovery of metronidazole activity in urine, as determined by this bioassay method, was somewhat less than one half (in normal volunteers) to one quarter (in patients with renal failure) of metronidazole plus metabolites as measured by HPLC. These discrepancies might be explained by the lower antibacterial activity of the hydroxy (congruent to 40%) and acetic acid (congruent to 2%) metabolites as compared with that of the parent compound in the test system used.

Once-daily dosing of acebutolol in hypertension.

Twenty-six patients with essential hypertension were admitted to a protocol comparing the efficacy of the once-a-day administration of acebutolol with twice-a-day administration. A placebo was substituted initially for their beta-blocker therapy. Other therapy was continued in 14 (11, diuretics alone; two, diuretics plus hydralazine or alpha-methyldopa; one, alpha-methyldopa alone). After 4 weeks, lying blood pressures were 160 +/- 16 (SD) mm Hg systolic, and 101 +/- 7 mm Hg diastolic. Incremental twice-a-day doses of acebutolol resulted in normotension (lying systolic, 131 +/- 12 mm Hg; diastolic, 84 +/- 5 mm Hg) in all 26 patients (eight on 400 mg, four on 600 mg, seven on 800 mg, one on 1,000 mg, and six on 1,200 mg/day). The same twice-a-day acebutolol dose was continued for two visits, 4 weeks apart, recording pressures at 8 a.m., 12 noon, 4 p.m., and 8 p.m.; followed by two visits, 4 weeks apart, while taking the total daily dose after the 8 a.m. recording. Blood pressures during once-a-day dosing were not different from those during twice-a-day dosing at any time. Highest pressures were at 8 a.m. and lowest were at 12 noon or 4 p.m. Variations during the day in both systolic and diastolic pressures were greater during once-a-day dosing. Plasma acebutolol and metabolite concentrations were proportional to the administered dose. Eighteen patients continued acebutolol for 1 year without adverse effects other than an asymptomatic positive antinuclear antibody test in six. Once-a-day dosing was as effective as twice-a-day dosing in this group of hypertensive patients.

Ethanol 'dose-dependent' elimination: Michaelis-Menten v classical kinetic analysis.

1 To compare classical linear regression techniques and a Michaelis-Menten elimination model eight normal human volunteers each received three intravenous doses (0.375, 0.5, and 0.75 g/kg) of ethanol and four of the subjects each received four oral doses (0.5, 0.65, 0.95, 1.25 g/kg) of ethanol. 2 Computerized analysis of the time-plasma concentration profiles using a two-compartment Michaelis-Menton elimination model yielded a median absorption constant of 1.29 h-1; volume of distribution of 0.47 l/kg; Vmax of 0.12 g h-1 kg-1; and Km of 0.03 g/l. Classical techniques resulted in a slope of 0.20 g l-1 h-1, volume of distribution of 0.55 l/kg, and a B60 of 0.11 g h-1 kg-1. 3 Transient post-prandial decreases in elimination slope occurred at higher oral doses. A trend of increasing slope with increasing oral dose was seen at concentrations well above the Km. Time to sobriety (0.8 g/l) increased nonlinearly with increasing peak concentration. 4 Maximal ethanol elimination rates are determined equally well by the two techniques. Classical analyses overestimate the volume of distribution of ethanol by 17%. Neither technique helps explain the post-prandial changes in slope or increasing slope with dose at high concentrations.

Cefoxitin disposition during peritoneal dialysis.

The pharmacokinetic disposition of 2 g of cefoxitin administered intravenously over 30 min was determined in six patients undergoing continuous ambulatory peritoneal dialysis for chronic renal failure. During the 6-h dialysate dwell time after the drug infusion, the mean apparent volume of distribution for cefoxitin was 0.267 liter/kg (range, 0.201 to 0.325 liter/kg), and the mean elimination t1/2 from plasma was 7.8 h (range, 5.5 to 13.1 h). The peritoneal clearance, averaging 1.51 ml/min (range, 0.58 to 2.35 ml/min), was only 7.4% of the mean plasmas clearance of cefoxitin. Cefoxitin clearance was reduced in patients with renal failure and was not increased by peritoneal dialysis.