| Background:Studies showed that efflux transporter P-GP is predominately expressed in the blood-brain barrier and it plays an important role in limiting the entry of drugs into the brain. It was reported that verapamil was the transporter substrates of P-GP, and some studies used verapamil as a inhibitor of P-GP (competitive binding mechanism). In vitro experiments fluconazole was confirmed as substrate of efflux transporter P-GP but there is no vivo experiment verified it. Blood-brain barrier dysfunction has been proposed to be involved in the pathological conditions of a variety of neurological diseases, but there is no study showed the changes of the blood-brain barrier in cerebral cryptococcus neoformans infection. Thecerebral microdialysis sampling had the continuous nature, and it can be used to directly sample molecules from the brain extracellular fluid (bECF) that makes microdialysis perfect for pharmacokinetic (PK) studies.Objective:The study is aimed to find out the changes of the blood-brain barrier in cerebral cryptococcus neoformans infection and to verified fluconazole is substrate of efflux transporter P-GP in vivo experiment.Methods:Divide all the rats into three group:group A is cryptococcus neoformans infection rats with only fluconazole injection, group B is cryptococcus neoformans infection rats with both fluconazole and verapamil injection, group C is natural rats with only fluconazole injection. The vivo microdialysis and high-performance liquid chromatographic method were used to study the drug concentration both in paracele and corpus striatum of the rats in different groups. DAS 2.0 software was used to analyze the pharmacokinetic parameters. The penetration rate of fluconazole in blood brain barrier (BBB) was defined as the the ratio of AUCbECF/AUCplasma and the penetration rate of fluconazole in blood cerebrospinal fluid barrier (BCSFB) was defined as the ratio of AUCCSF/AUCplasma. The different penetration rate of fluconazole in BBB and BCSFB of different groups can be the evidence to verify that fluconazole is substrate of efflux transporter P-GP.Results:The modeling success rate of the rats with tail vein injection of hydrocortisone is higher than those without the injection of hydrocortisone. The maximum concentration (Cmax) of fluconazole both in cerebrospinal fluid (CSF) (8.05±0.09 VS 7.18 ± 0.06, P=0.03) and striatum (5.2±0.04μg/mL VS 3.99±0.12μg/mL, P=0.01) are higher in cryptococcus neoformans infection rats with only fluconazole injection than normal rats with only fluconazole injection. The cryptococcus neoformans infection rats with both fluconazole and verapamil injection has higher Cmax of fluconazole in CSF 6.78± 0.10μg/mL VS 8.05±0.09μg/mL, P=1.20) than it is in cryptococcus neoformans infection rats with only fluconazole injection. There is no significant different in blood Cmax of fluconazole in the three groups (P=0.74, P=0.67).Conclusion:Intravenous injection of corticosteroids may increase the success rate of rats modeling cryptococcal meningitis model. The penetration rate of fluconazole in BBB is increased in the cerebral cryptococcus neoformans infection rats. Fluconazole is a substrate of efflux transporter-P-GP in vivo experiment. |
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