Pharmacokinetic Of Cycloserine In Healthy Rat Lungs And Brains By Microdialysis

The presumptuous spread of tuberculosis has seriously jeopardized the safety of ourpublic health. Prevention and treatment of tuberculosis as a public service career， relate tothe health and vital interests of the majority of patients with tuberculosis and othercitizens.There are many TB patients with drug resistance in China，they need a very longtime treatment of TB, often require multiple drugs used in combination. Cycloserine is amain drug in the treatment of MDR-TB. When cycloserine is about to enter the market, Tocarry out such a study is of great significance to the treatment of drug-resistant TB.Therapeutic Drug Monitoring (TDM) use a sensitive and reliable method to detect thepatient’s blood or other body fluids in drug concentration, and obtain the relevant pharmacokineticparameters, application of pharmacokinetic theory to guide rational drug use program development andadjustment, as well as drugsdiagnosis and treatment of poisoning to ensure the efficacy and safetyof the drug treatment。Therapeutic Drug Monitoring (TDM) represents a new area designed byclinicians, clinical pharmacologists and laboratory professionals collaborate to ensure that drug toachieve maximum therapeutic efficacy and minimal side effects of drugs. Currently, in the treatmentof tuberculosis.The drugs isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin andlevofloxacin carried out TDM in domestic and foreign area. There is none cycloserine reported in thelung tissue and brain tissue.Objective:By oral administration, using the microdialysis technique combined with High performanceliquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS)simultaneous determine of the concentration of free drug cycloserine specified time point in the ratlung，brain and blood, discover the characteristics of pharmacokinetics dynamics of cycloserine in rat lungs, brain tissue and blood.Preliminary discussing the pharmacodynamic of cycloserine inthe lungs and brain, and providing a basis for the anti-TB treatment.Materials and Methods:Twelve specific pathogen-flee male Sprague-Dawley rats were obtained andrandomly assigned to lung group or brain group．All animals were acclimatized in wirecages with a12：12h light-dark cycle for a minimum of5days before the beginning of theexperiment to allow them to adapt to the new environment．During this period，they hadflee access to food and water until18h prior to being supplied for experiments，at whichtime only food was removed．The program was administered via gastric canal then thedisposition of cycloserine in lung andblood，or in lung and brain，the dialysate were gatheredsimultaneously by the technique of microdialysis. It were used by HPLC-MS/MS toanalyze microdialysis samples．Pharmacokinetic calculations were performed on eachindividual set of date using the pharmacokinetic calculation software WinNonlin.Results：1.Group of the Lung：The maximum concentration of free cycloserine in blood andlung tissue were (10.61±2.42) mg/L and（1.53±1.71）mg/L at1h．then both continuouslydecreased.Concentration of free cycloserine in lung tissue was lower than that in blood allthe time，The area under the concentration curve(AUC)of unbound cycloserine was（33.53±6.51）h·mg-1·L-1in blood，and（9.19±3.48）h·mg·L-1in brain.Blood brain barrierpermeability of the drug was0.147±0.039, the highest value is0.338, the lowest value is0.146. Cycloserine in the blood and lung drug distribution coefficient was0.134±0.12。2. Group of the Brain：The maximum concentration of free cycloserine in blood andlung tissue were (10.58±4.74) mg/L at1.5h and（2.31±2.18）mg/L at1.25h．then bothcontinuously decreased. Concentration of free cycloserine in brain tissue was lower thanthat in blood all the time，The AUC of unbound cycloserine was（37.74±8.34）h·mg·L-1inblood，and（4.49±2.08）h·mg·L-1in lung.Blood lung barrier permeability of the drug was0.267±0.057, the highest value is0.285, the lowest value is0.105. Cycloserine in theblood and lung drug distribution coefficient was0.244±0.417。 Conclusion:Microdialysis sampling technology has a good spatial resolution, joint reversed-phaseHigh performance liquid chromatography-mass spectrometry/mass spectrometry is a goodtool for pharmacokinetic study in pancreatic tissue and blood pharmacokineticcharacteristics. The experiments show that, in the case of oral administration, cycloserine ahigher plasma concentration, but the poor lung tissue concentrations, the Penetration of theblood to the lungs is maintained at between0.105-0.285.Although the concentrations of the brains is higher than the lungs, it is notsignificantly. And penetration of the blood to the brains is maintained at between0.146-0.338.Combining to the MIC of Mycobacterium tuberculosis, Cycloserine play aweak role with a single administration of250mg against the tuberculosis in lung and brain.If necessary, increasing the dose can be considered of.