Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis.

We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmuno-assay (RIA) technique, lowering the limit of detection from 1.0 &mgr;g ml(minus sign1) to 0.05 &mgr;g ml(minus sign1). In 37 studies, after aerosol delivery of 666 plus minus 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 &mgr;g ml(minus sign1). Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol adminstration is 39.13 plus minus 0.393 L h(minus sign1) (mean plus minus standard error of the mean), with an elimination half-life of 3.072 plus minus 0.194 h. The half-life was significantly longer than that found after intravenous adminstration. The elimination rate constant (K(e)) was calculated to be 0.234 plus minus 0.002 h(minus sign1). Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 plus minus 0.002 1 hr(minus sign1) kg(minus sign1). We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m(minus sign2) dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.

Chloramphenicol is a substrate for a novel nitroreductase pathway in Haemophilus influenzae.

The p-nitroaromatic antibiotic chloramphenicol has been used extensively to treat life-threatening infections due to Haemophilus influenzae and Neisseria meningitidis; its mechanism of action is the inhibition of protein synthesis. We found that during incubation with H. influenzae cells and lysates, chloramphenicol is converted to a 4-aminophenyl allylic alcohol that lacks antibacterial activity. The allylic alcohol moiety undergoes facile re-addition of water to restore the 1,3-diol, as well as further dehydration driven by the aromatic amine to form the iminoquinone. Several Neisseria species and most chloramphenicol-susceptible Haemophilus species, but not Escherichia coli or other gram-negative or gram-positive bacteria we examined, were also found to metabolize chloramphenicol. The products of chloramphenicol metabolism by species other than H. influenzae have not yet been characterized. The strains reducing the antibiotic were chloramphenicol susceptible, indicating that the pathway does not appear to mediate chloramphenicol resistance. The role of this novel nitroreductase pathway in the physiology of H. influenzae and Neisseria species is unknown. Further understanding of the H. influenzae chloramphenicol reduction pathway will contribute to our knowledge of the diversity of prokaryotic nitroreductase mechanisms.

Montelukast pharmacokinetics in cystic fibrosis.

OBJECTIVES: To determine if patients with cystic fibrosis (CF) have an altered pharmacokinetic profile of montelukast, we studied the single-dose pharmacokinetics in 12 patients with CF and 12 age- and gender-matched controls after they received a 10-mg oral dose. METHODS: Plasma samples were collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours after drug administration. The specimens were analyzed by high-performance liquid chromatography (HPLC). RESULTS: The mean systemic clearance (mL/min) values (+/- SD) were not statistically different between the CF subjects (55.53 +/- 44.0 mL/min) and the controls (57.12 +/- 18.42 mL/min), nor were the results significantly different when normalized to body surface area or body weight. The mean value for elimination half-life, elimination rate constant, area under the plasma concentration versus time curve, and maximum concentration for controls was 2.37 +/- 0.38 hours, 0.30 +/- 0.05 hours(-1), 2,680.0 +/- 693.6 ng. min/mL, and 448.9 +/- 165.3 ng/mL; and for the CF patients it was 2.97 +/- 1.21 hours, 0.28 +/- 0.13 hrs(-1), 3976.1 +/- 2073.4 ng. min/mL, 606.7 +/- 237.8 ng/mL. There were no statistically significant differences (all P >.05) in the measured pharmacokinetic parameters between the CF and control subjects. CONCLUSIONS: We conclude that the dose of montelukast and the dosing interval does not need to be modified if the goal is to mimic the serum concentration used to treat asthma. The effectiveness of these concentrations for the inflammatory lung disease of patients with CF is unknown.

Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry.

We investigated the formation of PGF(2alpha) 1-ethanolamide, PGE(2) 1-ethanolamide, and PGD(2) 1-ethanolamide (prostamides F(2alpha), E(2), and D(2), respectively) in liver, lung, kidney, and small intestine after a single intravenous bolus administration of 50 mg/kg of anandamide to normal and fatty acid amide hydrolase knockout (FAAH -/-) male mice. One group of three normal mice was not dosed (naïve) while another group of three normal mice received a bolus intravenous injection of 50 mg/kg of anandamide. Three FAAH -/- mice also received an intravenous injection of 50 mg/kg of anandamide. After 30 min, the lung, liver, kidney, and small intestine were harvested and processed by liquid-liquid extraction. The concentrations of prostamide F(2alpha), prostamide E(2), prostamide D(2), and anandamide were determined by HPLC-tandem mass spectrometry. Prostamide F(2alpha) was detected in tissues in FAAH -/- mice after administration of anandamide. Concentrations of anandamide, prostamide E(2), and prostamide D(2) in liver, kidney, lung, and small intestine were much higher in the anandamide-treated FAAH -/- mice than those of the anandamide-treated control mice. This report demonstrates that prostamides, including prostamide F(2alpha), were formed in vivo from anandamide, potentially by the cyclooxygenase-2 pathway when the competing FAAH pathway is lacking.