Linezolid absolute bioavailability and the effect of food on oral bioavailability.

Linezolid is a novel oxazolidinone antibiotic that has a spectrum of activity encompassing a variety of Gram-positive bacteria. The objectives of this study were twofold: (1) to compare the absorption of linezolid tablets given immediately following a high-fat meal with the absorption of tablets administered while fasting, and (2) to assess the bioavailability of a 375-mg oral dose given while fasting relative to a 375-mg dose of linezolid sterile solution given intravenously. Venous blood samples were taken over the 48 h following the single dose administration of both the oral and intravenous (IV) treatment. Samples were subsequently frozen for the determination of linezolid concentrations by HPLC. The only statistically significant difference between the fasted and the fed treatment was in peak plasma concentration, with the mean C(max) for fasted subjects being 23% greater than that for subjects after consumption of a high-fat meal. Comparable AUC(0-infinity) values were measured under both conditions, indicating that the overall extent of absorption is the same. Therefore, the difference in C(max), while statistically significant, should not affect the therapeutic efficacy of linezolid when it is administered with food. There were no statistically significant differences in AUC(0-infinity), CL or half-life between the fasted oral treatment and the intravenous treatment. As expected, C(max) was statistically different between the two treatments. However, the mean absolute bioavailability (F) of the tablet, using the IV sterile solution as the reference treatment, was 103% (+/-20%).

Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects.

Linezolid (Zyvox), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections, including resistant strains. The disposition of linezolid in human volunteers was determined, after a 500-mg (100-microCi) oral dose of [(14)C]linezolid. Radioactive linezolid was administered as a single dose, or at steady-state on day 4 of a 10-day, 500-mg b.i.d. regimen of unlabeled linezolid (n = 4/sex/regimen). Mean recovery of radioactivity in excreta was 93.8 +/- 1.1% (range 91.2-95.2%, n = 15), of which 83.9 +/- 3.3% (range 76.7-88.4%) was in urine and 9.9 +/- 3.4% (range 5.3-16.9%) was in feces. There was no major difference in rate or route of excretion of radioactivity by dose regimen. Linezolid was excreted primarily intact, and as two inactive, morpholine ring-oxidized metabolites, PNU-142586 and PNU-142300. Other minor metabolites were characterized by high-performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry and (19)F NMR spectroscopy. After the single radioactive dose, linezolid was the major circulating drug-related material accounting for about 78% (male) and 93% (female) of the radioactivity area under the curve (AUC). PNU-142586 (T(max) of 3-5 h) accounted for about 26% (male) and 9% (female) of the radioactivity AUC. PNU-142300 (T(max) of 2-3 h) accounted for about 7% (male) and 4% (female) of the radioactivity AUC. Overall, mean linezolid and PNU-142586 exposures at steady-state were similar across sex. In conclusion, linezolid circulates in plasma mainly as parent drug. Linezolid and two major, inactive metabolites account for the major portion of linezolid disposition, with urinary excretion representing the major elimination route. Formation of PNU-142586 was the rate-limiting step in the clearance of linezolid.

Carnitine supplementation of parenterally fed neonates.

BACKGROUND: Carnitine, a quaternary amino acid, plays an important role in the oxidation of long chain fatty acids. Both breast milk and infant formulas contain carnitine. However, it is not routinely provided in parenteral nutrition solutions. Non supplemented parenterally fed infants have very low tissue carnitine levels. The clinical significance of this is uncertain. Carnitine deficiency may be an etiological factor in the limited ability of premature babies to utilize parenteral lipid. In vitro studies have suggested that fatty acid oxidation is impaired when the tissue carnitine levels fall below 10% of normal. Therefore relative carnitine deficiency may impair fatty acid oxidation, thus reducing the available energy and impairing growth. OBJECTIVES: The primary aim of this review is to determine whether carnitine supplementation of parenterally fed neonates will improve weight gain. The secondary aims are to determine the effect on lipid tolerance and ketogenesis. SEARCH STRATEGY: Computerised searches were carried out by both reviewers. Searches were made of Medline, Embase, The National Research Register (UK), the Cochrane Controlled Trials Register and expert informants. The MeSH headings used were carnitine and parenteral nutrition. SELECTION CRITERIA: Only randomised trials were considered. Trials were included if they involved carnitine supplementation alone, parenterally fed newborn infants, and measured at least one outcome of interest (weight gain, plasma fatty acids, plasma triglycerides, quantity of lipid tolerated, respiratory quotient or beta hydroxybutyrate levels). DATA COLLECTION AND ANALYSIS: The two reviewers searched the literature separately and reached a consensus for inclusion of trials. Data were extracted and evaluated by the two reviewers independently of each other. Authors were contacted if possible to clarify or provide missing data. MAIN RESULTS: Fourteen studies were identified, six met the selection criteria. The results of the review are limited by the fact that the studies were generally short term and studied different outcomes. One study examined short term and long term weight gain, three reported only short term weight gain, three reported biochemical results in response to a short lipid challenge, and two reported results obtained during normal parenteral nutrition. Among infants supplemented with carnitine, there was no evidence of effect on weight gain, lipid utilization or ketogenesis. REVIEWER'S CONCLUSIONS: We found no evidence to support the routine supplementation of parenterally fed neonates with carnitine.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Population pharmacokinetics of glyburide in patients with well-controlled diabetes.

STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

Solubility enhancement of phenol and phenol derivatives in perfluorooctyl bromide.

Perfluorinated solvents are gaining popularity as pulmonary ventilation fluids, but they suffer from poor solvent quality in concurrent drug delivery applications. The present study examines the use of a hydrophobic solubilizing agent capable of interacting with model drug solutes by hydrogen bonding with the purpose of enhancing solubility in perfluorooctyl bromide (PFOB). A series of solubilizing agents containing a ketone carbonyl to act as a hydrogen bond acceptor and a perfluoroalkyl chain to maintain the solubility of the putative complex in PFOB are investigated. The solubility of phenol in PFOB is enhanced to the greatest extent by 1-(4-perfluorobutyl phenyl)-1-hexanone (III) where the ketone carbonyl is protected from the electron withdrawing effects of the perfluorobutyl chain by a phenyl ring. Experiments with solubilizers lacking the ketone group suggest that pi-pi bond interactions of III with phenol do not significantly enhance solubility. For a series of phenol derivatives, a rank-order correlation exists between the magnitude of solubility enhancement by III, as reflected by the calculated association constants, and the Hammett sigma parameter of the phenols. Because the O-methyl-substituted phenols do not have the ability to hydrogen bond, their solubility is not enhanced by the presence of III. The results of the present study indicate that solubility of model drug hydrogen bond donating compounds can be enhanced in PFOB by the presence of fluorocarbon-soluble hydrogen bond acceptors.

Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones eperezolid and linezolid.

In Phase I trials subjects received multiple doses of eperezolid (PNU-100592; formerly U-100592) and linezolid (PNU-100766; formerly U-100766), and steady-state samples were drawn at the projected peak and trough timepoints. Serum inhibitory titer and serum bactericidal titer values were determined using single strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Serum inhibitory titer values generally correlated with drug concentration in serum and inherent organism susceptibility. Against S. aureus and E. faecalis sera from patients dosed with either drug were generally inhibitory at the peak timepoint, but at trough only linezolid exhibited a persistent effect. No bactericidal activity was seen for either drug against S. aureus or E. faecalis. The sera from patients dosed with either drug exhibited inhibition of S. pneumoniae at peak and trough. Bactericidal activity was seen against S. pneumoniae for both drugs at peak time and at trough for many of the sera for patients on the higher dose regimens. The results demonstrated that the sera from most human subjects dosed with eperezolid or linezolid were inhibitory to S. aureus and E. faecalis and S. pneumoniae and that many of the samples exhibited bactericidal activity for S. pneumoniae.

Pharmacokinetics of oral glyburide in subjects with non-insulin-dependent diabetes mellitus and renal failure.

To test the hypothesis that renal failure has no effect on the pharmacokinetics of glyburide, five subjects with non-insulin-dependent diabetes mellitus (NIDDM) and end-stage renal disease requiring hemodialysis, and four NIDDM subjects with normal renal function were studied. On days 0, 1, and 15, subjects consumed 33 carbohydrate grams, and glucose, insulin, and C-peptide were measured for 4 hours. On day 1, subjects received 3 mg glyburide and measured plasma concentrations for 48 hours. On day 3, multiple dosing on 3 mg glyburide daily began. On day 15, plasma concentrations were measured for 48 hours. The pharmacokinetics and pharmacodynamics of glyburide, glucose, insulin, and C-peptide were determined as well as daily fasting blood glucose. Glucose area under the curve (AUC) and daily fasting glucose levels did not change in either controls or hemodialysis subjects. The mean serum glyburide blood levels and pharmacokinetics did not differ after initial or chronic glyburide administration in NIDDM subjects with end-stage renal disease treated with hemodialysis compared with controls. Glyburide half-life averaged 3.3 hours in control subjects and 5.0 hours in hemodialysis subjects. Hemodialysis subjects had increased C-peptide and insulin AUC with chronic dosing. Renal failure does not affect the pharmacokinetics of 3.0 mg oral glyburide.