Zidovudine concentration in brain exracellular fluid measured by microdialysis:steady-stae and transient results in rhesus monkey

摘要

We measured aicovudine concenrations in blood,muscle,and brain extracellular fluid (ECF) by microdialysis and in serum ultrafiltrate and cerebrospinal fluid (CSF) samples during a continuous intravenous infusion (15 mg/kg/h) and after bolus dosing (50-80 mg/kg over 15 min) in nonhuman primates to determine whether SCF drug penetration is a valid surrogate for blood-brainbarrier penetration.Recovery was estimated in vivo by zero net flux ofr the continuous infusion and retrodialysis for the bolus dosing.Invivo recovery was tissue-dependent and was lower in brain thanin blood or muscle.Mean(+-S.D.) steady-state blood,muscle,and brainzidovudine concentrations by microdialysis were 112+-63.8,105+-51.1,and 13.8+-10.4 #mu#M,respectivley;and steady-state serum ultrafiltrate and CSF concentrations were 81.2+-40.2 and 14.1+-8.0 #mu#M,respectively.Brain ECF penetration(microdialysis brain/blood ratio) and CSF penetration(Standard sampling CSF/serum ratio)at steady state were 0.13+-0.06 and 0.17+-0.02,respectively.Withbolus diosing the mean (+-S.D.) zidkovudine area under concentration-timecurve (AUC) normalized to a dose of 80 mg/kg was 577+-103 #mu#Mcentre dothinblood,528+-202 #mu#Mcentre doth in muscle,and 108+-74 #mu#Mcentre doth in brain(brain/blood ratio of 0.18+-0.10) by microdialysis.Serum ultrafiltrate AUC was 446+-72#mu#Mcentre doth and the CSF AUC was 123+-4.7#mu#Mcentre doth(CSF/serum ratio of 0.28+-0.06).In conclusion,recovery was tissue-dependent.CSF and brainECF zidovudine concentrations were comparable at steadystate,and the corresponding AUCs were comparable after bolus injection.Thus,zidovudine penetration in brain ECF and CSF in nonhuman primates is limited to a similar extent,presumably by active transport,as inother species.