Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery.

OBJECTIVES: Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS: In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS: After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg ·â€Šh/L after oral dosing and 52.3 ± 1.3 mg ·â€Šh/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS: This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Switch from intravenous to enteral moxifloxacin in critically ill patients: a pilot study.

Critically ill patients generally receive moxifloxacin intravenously to achieve rapid bacterial killing. An early switch from intravenous to enteral moxifloxacin may be considered because of its good oral bioavailability in healthy volunteers. Since bioavailability may be altered in critically ill patients due to pathophysiological changes, this study aimed to investigate whether enteral moxifloxacin is bioequivalent to intravenous moxifloxacin in such patients. Blood samples were obtained from 4 critically ill patients before and at serial time-points after intravenous and enteral administration. In all patients, lower maximum plasma concentration (C(max)) and area under the plasma concentration-time curve during the 24-h observation period (AUC(24h)) values were observed after enteral administration compared to those after intravenous administration. This resulted in lower C(max)/minimum inhibitory concentration (MIC) and AUC(24h)/MIC values, which are 2 indices predicting the antibacterial efficacy of moxifloxacin. Despite the limited number of subjects, we conclude that a switch from intravenous to enteral moxifloxacin is not recommended in these patients, because the 2 administration forms are not bioequivalent.

Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems.

AIMS: Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (MUPS® formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems. METHODS: Nonblinded, two-phase cross-over trial. RESULTS: In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS® formulation. Median (90% confidence interval) area under the plasma concentration-time curve ratio (MUPS® over suspension) was 0.5 (0.06-2.37). CONCLUSIONS: In this population, omeprazole MUPS® formulation has no apparent advantage over the more easily administered suspension formulation.

A bio-analytical hydrophilic interaction LC-MS/MS method for the simultaneous quantification of omeprazole and lansoprazole in human plasma in support of a pharmacokinetic omeprazole study in children.

A hydrophilic interaction LC method with MS/MS was developed and validated for the simultaneous quantification of omeprazole and lansoprazole in human plasma. Chromatographic separation was achieved on a Betasil silica column using a high organic mobile phase (eluent A: ACN/formic acid 997.5:2.5 v/v; eluent B: water/formic acid 997.5:2.5 v/v) and gradient elution. The mass spectrometer was operated in the Multiple Reaction Monitoring mode. Prior to chromatography, liquid-liquid extraction with ethyl acetate was used and the organic layer was diluted with ACN, allowing direct injection on column. The method showed acceptable linearity, high precision (RSD%<10.5%), accuracy (88.9-109.3%) and selectivity in the two concentration ranges studied: 1.5-100 and 5-2000 ng/mL. The LOQ was established at 1.5 and 5 ng/mL for the two concentration ranges. Lack of variability in matrix effects was demonstrated and mean extraction recovery for omeprazole and lansoprazole was determined in the low (56.3-67.7%) and high (45.3-44.3%) concentration range, respectively. Additionally, plasma samples were found to be stable after three freeze-thaw cycles and for at least 15 h after extraction. This assay was successfully applied to a pharmacokinetic omeprazole study in children with cerebral palsy and mental retardation.

Disulfiram inhibition of cyanide formation after acetonitrile poisoning.

CONTEXT: Cyanide poisoning may be caused by acetonitrile, a common industrial organic solvent and laboratory agent. OBJECTIVE: To describe the potential use of disulfiram in treating acetonitrile poisoning in a human clinical case and to further study its effect in human liver microsomes in vitro. CASE DETAILS: A 30-year-old man initially presented with a cholinergic toxic syndrome following ingestion of aldicarb. Toxicological analysis revealed coingestion of ethanol. He subsequently developed severe metabolic acidosis caused by the cyanogenic compound acetonitrile which was erroneously interpreted as acetone in the chromatogram. After three treatments with hydroxocobalamin (5 g i.v.) and sodium thiosulfate (12.5 g i.v.) on days 2, 3, and 5, he had transient improvement but recurrent lactic acidosis. Treatment with disulfiram was associated on day 7 with resolution of metabolic acidosis and slowing of the decrease in acetonitrile concentration. He recovered from acetonitrile toxicity completely. The time course of acetonitrile, thiocyanate, and cyanide concentrations suggested that disulfiram inhibited cyanide formation. RESULTS: In vitro experiments with human liver microsomes showed the cyanide concentration was significantly lower after incubation with acetonitrile and disulfiram than acetonitrile alone (a mean 60% reduction in cyanide level). DISCUSSION: Although disulfiram was given late in the course of the poisoning it is possible that it contributed to the recovery.

The influence of bypass procedures and other anatomical changes in the gastrointestinal tract on the oral bioavailability of drugs.

The gastrointestinal (GI) tract plays an important role in the absorption of orally administered drugs. However, in some cases the anatomy of the GI tract is changed due to GI surgery, which has the potential of influencing drug bioavailability. In this review, we aim to compile, review, and comment the existing but sometimes fragmented scientific data regarding the impact of GI surgery on the oral bioavailability of drugs. Relevant reports were gathered through the PubMed database from database inception through January 2012. Drugs for which at least one trial or case report suggested a change in oral bioavailability or absorption caused by GI surgery are discussed in detail. Major methodological differences, such as study design, number of subjects and choice of reference group, were observed in the reported studies. Predicting the impact of GI surgery on the oral bioavailability was therefore difficult to perform, even the most sophisticated classification systems could not be used for predicting purposes.

Development and validation of a fast and sensitive UPLC-MS/MS method for the quantification of six probe metabolites for the in vitro determination of cytochrome P450 activity.

A fast and sensitive UPLC-MS/MS method was developed and validated for the simultaneous quantification of six probe metabolites for the in vitro cytochrome P450 activity determination in hepatic microsomes from patients with hepatic impairment. The metabolites acetaminophen (CYP1A2), 4'-hydroxy-mephenytoin (CYP2C19), 4-hydroxy-tolbutamide (CYP2C9), dextrorphan (CYP2D6), 6-hydroxy-chlorzoxazone (CYP2E1) and 1-hydroxy-midazolam (CYP3A4), together with the internal standard chlorpropamide, were separated on a Waters Acquity UPLC BEH C18 column (50 mm × 2.1mm, 1.7 µm particle size) with VanGuard pre-column (5 mm × 2.1mm, 1.7 µm particle size). A short gradient elution (total run time of 5.25 min), using water with 0.1% formic acid (eluent A) and acetonitrile with 0.1% formic acid (eluent B) at a flow rate of 400 µl/min, was used. The metabolites were detected with a triple quadrupole mass spectrometer in the multiple reaction monitoring mode. Two runs, one in the positive ionization mode and one in the negative mode, were necessary for the detection of all metabolites. The method was selective and showed good accuracy (84.59-109.83%) and between-day (RSD%<5.13%) and within-day (RSD%<9.60%) precision. The LOQ was in full accordance with the intended application, and no relative matrix effects were observed. Also, the sample incubation extracts were stable after three freeze-thaw cycles. The usability of the method was demonstrated by the incubation of pediatric microsomes with subsequent quantification of the formed metabolites and CYP activity calculation.

Impact of corneal cross-linking on drug penetration in an ex vivo porcine eye model.

PURPOSE: To analyze the influence of corneal cross-linking (CXL) using ultraviolet-A and riboflavin on corneal drug penetration of topically applied drugs. METHODS: In an ex vivo porcine eye model, eyes were randomly assigned to CXL or control treatment. Central corneal thickness and anterior chamber depth were measured with a Pentacam device. In the CXL group, eyes were treated with CXL using ultraviolet-A (370 nm) and riboflavin, whereas in the control group only riboflavin was applied without irradiation. Subsequently, 0.3% ofloxacin (n = 40 eyes) or 1% voriconazole (n = 40 eyes) eye drops were applied to the cornea every 5 minutes for 30 minutes. Aqueous humour samples were obtained performing an anterior chamber tap. The concentrations of ofloxacin and voriconazole were determined with high-pressure liquid chromatography. Groups were compared performing a Mann-Whitney test. RESULTS: In the CXL group, the mean concentration of ofloxacin (13.33 ± 4.67 µg/mL) and voriconazole (52.70 ± 8.76 µg/mL) was significantly lower than in the untreated control group (ofloxacin: 18.51 ± 6.08 µg/mL, P = 0.005; voriconazole: 62.43 ± 13.5 µg/mL, P = 0.01). This corresponds to a reduction in permeability of 27.98% for ofloxacin and 15.59% for voriconazole. Central corneal thickness and anterior chamber depth were comparable in the CXL and control groups (P > 0.05, each). CONCLUSIONS: CXL reduces the corneal permeability of ofloxacin and voriconazole. This may be of clinical significance, for example, in keratitis treatment.

Pharmacokinetics of fluoroquinolones in critical care patients: A bio-analytical HPLC method for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed and validated for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma. Sarafloxacin was used as internal standard. Chromatography was carried out using a Waters XBridge C(18) HPLC column and a gradient mobile phase consisting of CH(3)CN/MeOH/0.025M TBA.Cl/TFA (eluent A at 75/25/899/1 (v/v); eluent B at 150/50/799/1 (v/v); both at pH 3.5). Excitation/emission wavelengths were 279/442nm for ciprofloxacin and 290/500nm for ofloxacin, moxifloxacin and internal standard. Prior to chromatography, plasma samples were treated with acetonitrile for protein precipitation, followed by evaporation of the liquid layer and reconstitution in eluent A. The method was validated for the three fluoroquinolones over the clinically relevant concentration range from 0.02 to 7.50mug/ml. The method showed acceptable linearity with correlation coefficients, r(2)>0.995, as well as high precision (RSD% <7% in each case), accuracy (90.4-105.4%) and selectivity. The limit of quantification for the three fluoroquinolones was established at 0.02mug/ml. Ofloxacin, ciprofloxacin and moxifloxacin were extracted from plasma with a mean recovery of 95%, 86.4% and 94.2%, respectively. During validation, the concentration of the three fluoroquinolones was found to be stable after 3 freeze-thaw cycles and for at least 15h after extraction. This bio-analytical method was finally applied to the analysis of samples which have been obtained from patients, participating in a pharmacokinetic study on moxifloxacin.