| BackgroundThe blood-brain barrier(BBB)plays an essential role in regulating the homeostatic microenvironment of the brain.Broadly speaking,the BBB include the blood-cerebrospinal fluid barrier(BCSFB),the arachnoid barrier,and the BBB itself.The BBB lies at the interface between the blood and the brain interstitial fluid,while the BCSFB lies at the interface between the blood and the cerebrospinal fluid(CSF).One of the defining characteristics of the BBB and the BCSFB is the presence of membrane transport proteins.Most of these proteins belong to the family of adenosine triphosphate-binding cassette transporters and the superfamily of solute transporters.Among them,P-glycoprotein(P-gp),breast cancer resistance protein(Bcrp),multidrug resistance-associated proteins(Mrps),and organic anion transporters(Oats)are the most widely known and well characterized.Acyclovir,ganciclovir and ceftriaxone are commonly recommended as the first-line regimens for several central nervous system infectious diseases such as herpes simplex encephalitis and bacterial meningitis.However,whether P-gp,Bcrp,Mrps,and Oats play roles in the penetration of acyclovir,ganciclovir,and ceftriaxone across the BBB and the BCSFB remains unclear.Objective1.To confirm the Kp,uu,brain and Kp,uu,CSF of acyclovir,ganciclovir,and ceftriaxone.2.To investigate the mechanisms of membrane transport proteins(P-gp,Bcrp,Mrps and Oats)in the penetration of acyclovir,ganciclovir,and ceftriaxone across the BBB and the BCSFB.Methods1.After striatum,lateral ventricle,and blood microdialysis modeling,rats were randomly assigned to six groups(n=10 per group,five for brain microdialysis,and the other five for blood microdialysis):blank control group,vehicle control group,P-gp inhibition group,Bcrp inhibition group,Mrps inhibition group,and Oats inhibition group.For blank control group,rats were administrated with acyclovir(50 mg/kg,intraperitoneal injection[i.p.]).For vehicle control group,rats were pretreated with vehicle(2 mL/kg,i.p.)30 min before acyclovir administration(50 mg/kg,i.p.).For P-gp inhibition group,rats were pretreated with tariquidar(8 mg/kg,i.p.)30 min before acyclovir administration(50 mg/kg,i.p.).For Bcrp inhibition group,rats were pretreated with Ko143(15 mg/kg,i.p.)30 min before acyclovir administration(50 mg/kg,i.p.).For Mrps inhibition group,rats were pretreated with MK571(10 mg/kg,i.p.)30 min before acyclovir administration(50 mg/kg,i.p.).For Oats inhibition group,rats were pretreated with probenecid(50 mg/kg,i.p.)and vehicle(2 mL/kg,i.p.)30 min before acyclovir administration(50 mg/kg,i.p.).Microdialysis samples were collected at 15 min intervals for 120 min post acyclovir administration and analyzed by high-performance liquid chromatography(HPLC)immediately.Pharmacokinetic parameters,including unbound brain-to-blood concentration ratio(Kp,uu,brain)and unbound CSF-to-blood concentration ratio(Kp,uu,CSF)were calculated using Phoenix WinNonlin Version 8.2.0.2.After striatum,lateral ventricle,and blood microdialysis modeling,rats were randomly assigned to six groups(n=10 per group,five for brain microdialysis,and the other five for blood microdialysis):blank control group,vehicle control group,P-gp inhibition group,Bcrp inhibition group,Mrps inhibition group,and Oats inhibition group.For blank control group,rats were administrated with ganciclovir(30 mg/kg,i.p.).For vehicle control group,rats were pretreated with vehicle(2 mL/kg,i.p.)30 min before ganciclovir administration(30 mg/kg,i.p.).For P-gp inhibition group,rats were pretreated with tariquidar(8 mg/kg,i.p.)30 min before ganciclovir administration(30 mg/kg,i.p.).For Bcrp inhibition group,rats were pretreated with Ko143(15 mg/kg,i.p.)30 min before ganciclovir administration(30 mg/kg,i.p.).For Mrps inhibition group,rats were pretreated with MK571(10 mg/kg,i.p.)30 min before ganciclovir administration(30 mg/kg,i.p.).For Oats inhibition group,rats were pretreated with probenecid(50 mg/kg,i.p.)and vehicle(2 mL/kg,i.p.)30 min before ganciclovir administration(30 mg/kg,i.p.).Microdialysis samples were collected at 15 min intervals for 120 min post ganciclovir administration and analyzed by HPLC immediately.Pharmacokinetic parameters,including Kp,uu,brain and Kp,uu,CSF were calculated using Phoenix WinNonlin Version 8.2.0.3.After striatum,lateral ventricle,and blood microdialysis modeling,rats were randomly assigned to six groups(n=10 per group,five for brain microdialysis,and the other five for blood microdialysis):blank control group,vehicle control group,P-gp inhibition group,Bcrp inhibition group,Mrps inhibition group,and Oats inhibition group.For blank control group,rats were administrated with ceftriaxone sodium(200 mg/kg,intravenous infusion[i.v.]).For vehicle control group,rats were pretreated with vehicle(2 mL/kg,i.p.)30 min before ceftriaxone sodium administration(200 mg/kg,i.v.).For P-gp inhibition group,rats were pretreated with tariquidar(8 mg/kg,i.p.)30 min before ceftriaxone sodium administration(200 mg/kg,i.v.).For Bcrp inhibition group,rats were pretreated with Ko143(15 mg/kg,i.p.)30 min before ceftriaxone sodium administration(200 mg/kg,i.v.).For Mrps inhibition group,rats were pretreated with MK571(10 mg/kg,i.p.)30 min before ceftriaxone sodium administration(200 mg/kg,i.v.).For Oats inhibition group,rats were pretreated with probenecid(50 mg/kg,i.p.)and vehicle(2 mL/kg,i.p.)30 min before ceftriaxone sodium administration(200 mg/kg,i.v.).Microdialysis samples were collected at 15 min intervals for 120 min post ceftriaxone sodium administration and analyzed by HPLC immediately.Pharmacokinetic parameters,including Kp,uu,brain and Kp,uu,CSF were calculated using Phoenix WinNonlin Version 8.2.0.Results1.For rats administered acyclovir alone,the Kp,uu,brain and Kp,uu,CSF of acyclovir was 14.6± 0.8%and 25.6 ± 1.8%,respectively.For rats administered ganciclovir alone,the Kp,uu,brain and Kp,uu,CSF of ganciclovir was 14.1 ± 2.5%and 21.4 ± 2.0%,respectively.For rats administered ceftriaxone sodium alone,the Kp,uu,brain and Kp,uu,CSF of ceftriaxone was 10.2 ±1.0%and 17.8 ± 1.3%,respectively.2.For rats pretreated with tariquidar,the Kp,uu,brain of acyclovir increased by 1.5-fold(22.3 ± 1.8%,P<0.01),but no modification in the Kp,uu,CSF of acyclovir was found.For rats pretreated with tariquidar,the Kp,uu,brain and Kp,uu,CSF of ganciclovir increased by 2.0-fold(31.0± 2.1%,P<0.01)and 1.5-fold(32.5 ± 2.9%,P<0.01),respectively.For rats pretreated with tariquidar,the Kp,uu,brain and Kp,uu,CSF of ceftriaxone increased by 2.2-fold(22.5 ± 1.2%,P<0.01)and 1.5-fold(26.0±1.6%,P<0.01),respectively.3.For rats pretreated with Ko 143,the Kp,uu,brain and Kp,uu,CSF of acyclovir increased by 1.7-fold(23.8 ± 2.9%,P<0.01)and 1.8-fold(43.5 ± 4.3%,P<0.01),respectively.For rats pretreated with Ko143,the Kp,uu,brain and Kp,uu,CSF of ganciclovir increased by 1.7-fold(26.0 ±1.3%,P<0.01)and 1.8-fold(40.1 ± 3.0%,P<0.01),respectively.For rats pretreated with Ko143,the Kp,uu,brain and Kp,uu,CSF of ceftriaxone increased by 1.8-fold(18.9 ± 0.8%,P<0.01)and 2.4-fold(41.3 ± 5.5%,P<0.01),respectively.4.For rats pretreated with MK571,the Kp,uu,brain of acyclovir increased by 1.4-fold(20.6± 0.6%,P<0.01),but no modification in the Kp,uu,CSF of acyclovir was found.For rats pretreated with MK571,the Kp,uu,brain and Kp,uu,CSF of ganciclovir increased by 2.1-fold(31.6 ±2.0%,P<0.01)and 1.2-fold(25.8 ± 1.3%,P=0.01),respectively.For rats pretreated with Ko143,the Kp,uu,brain and Kp,uu,CSF of ceftriaxone increased by 1.5-fold(15.2 ± 1.4%,P<0.01)and 1.3-fold(22.3 ± 0.8%,P<0.01),respectively.5.For rats pretreated with probenecid,no modification in the Kp,uu,brain and Kp,uu,CSF of acyclovir,ganciclovir and ceftriaxone was found.Conclusion1.The Kp,uu,brain of acyclovir,ganciclovir and ceftriaxone is lower than the Kp,uu,CSF of these drugs,respectively.This phenomenon may be related to differences in the expression,distribution,and function of P-gp on the BBB and BCSFB.2.P-gp,Bcrp and Mrps play a role in the efflux of acyclovir,ganciclovir and ceftriaxone from the brain interstitial fluid to the blood.3.Bcrp plays a role in the efflux of acyclovir,ganciclovir and ceftriaxone from the CSF to the blood.4.Oats has no effect on the penetration of acyclovir,ganciclovir and ceftriaxone across the BBB and the BCSFB5.Mrps may play a role in the efflux of ganciclovir from the CSF to the blood. |
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