A reversed-phase high-performance liquid chromatography assay was developed and validated to determine plasma and brain lamotrigine concentrations allowing pharmacokinetic-pharmacodynamic studies of this new antiepileptic drug in patients and laboratory animals. Lamotrigine and its internal standard were extracted, under alkaline conditions, from plasma and brain homogenate, into ethyl acetate; brain proteins were previously precipitated with trichloroacetic acid. The method was linear between 0.1 and 15.0 mg / l for plasma, with a detection limit of 0.008 mg / l, and between 0.1 and 5.0 mg / l for brain homogenate, with a detection limit of 0.023 mg / l. The method proved to be simple, useful and appropriate, not only for clinical and experimental research, but also for routine monitoring of lamotrigine concentrations in patients.

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Vancomycin dispositions in the respiratory system were compared after systemic and inhalatory administration under two respiratory conditions using the isolated-lung model. Inhalatory delivery led to much higher drug levels in pulmonary tissue and fluids. The respiratory pattern affects vancomycin disposition in the pulmonary system regardless of the administration route.Pulmonary drug delivery is an efficient method for the passive targeting of drugs used in the treatment of pulmonary diseases such as asthma, bronchitis, emphysema, and respiratory infections. Nebulization of antibiotics has relevant advantages compared to other administration modes: drug access to all regions of the respiratory system, prolonged delivery periods, and the avoidance of extensive systemic exposure to drugs are some of the most interesting features of this practice (6, 9). Vancomycin is a glycopeptide drug indicated for the treatment of serious, life-threatening infections caused by gram-positive bacteria that are unresponsive to other, less toxic antibiotics (11,17), and this is the drug of choice for the treatment of bronchopneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), particularly in the case of patients undergoing mechanical ventilation (3). Renal impairment and ototoxicity are the most significant side effects, being the consequences of excessive drug accumulation (15). Owing to the interest in obtaining information about vancomycin disposition after pulmonary delivery, the aims of the present study were to compare the kinetics of this glycopeptide in the pulmonary system after systemic and inhalatory delivery and to evaluate the influence of the respiratory pattern on administration by both routes.Experimental protocol. Twenty-four male Wistar rats with a mean body weight of 239.89 Ϯ 19.96 g were used. Twelve hours prior to the experiments, the animals were isolated in cages and allowed access to tap water ad libitum. The housing and experimental treatment of animals were in accordance with the current Spanish legislation and complied with the principles of laboratory animal care. The animals were randomly distributed into four groups: (i) systemic administration, 60 respirations per minute (rpm), 8.4-ml/kg tidal volume; (ii) systemic administration, 30 rpm, 16.7-ml/kg tidal volume; (iii) inhalatory administration, 60 rpm, 8.4-ml/kg tidal volume; and (iv) inhalatory administration, 30 rpm, 16.7-ml/kg tidal volume. The inspiration/expiration ratio was 0.8. The method used to isolate lungs and to keep them artificially perfused and mechanically ventilated has been described in depth previously (13). A dose of 500 g of vancomycin was administered by the systemic or inhalatory route. For pulmonary administration, 700 g of drug was dissolved in 7 ml of distilled water. Nebulization was performed using a nebulizer device (ultrasonic aerosol generator 700700-UV TSE system) connected to the artificial ventilation system in such a way that 5 ml reached the lungs through the cannula for 20 min (nebulization flow ...

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