Study On The Pharmacokinetics Of Acetaminophen In The Frontal Cortex And Blood Of Rats

Objectives: To explore the studying method for pharmacokinetics at drug target-sites,the pharmacokinetic processes of acetaminophen in the blood and frontal cortex (FrCx)extracellular fluid of rats were investigated, respectively.Methods:①Microdialysis sampling:Male SD rats (280-320g) were anaesthetized(urethane,1.2g/kg, i.p.) and secured in a stereotaxic frame. A microdialysis probewas implanted into the FrCx and perfused with artificial cerebrospinal fluid (aCSF) ata flow rate of2μL/min. One hour later, rats were administrated (i.p.) of acetaminophen(200mg/kg) and dialysates were collected continuously at12-min intervals (24μLeach) for6h. The dialysates were kept at-40°C for assayed.②Blood sampling: afteranaesthetized with urethane (1.2g/kg, i.p.) rats were inserted with a catheter in thecarotid artery for collecting blood samples. After one hour, rats were administrated(i.p.) of acetaminophen (200mg/kg), and300μL blood (each rat) was collectedfrom the carotid artery at0.08h,0.25h,0.5h,0.75h,1.0h,2.0h,4.0and6.0h,respectively, after administration. These blood samples were heparinized and kept at-40°C for analyzed. The acetaminophen concentration in these samples obtained by thetwo methods described above was determined by HPLC-Ultraviolet detection. Theconcentration-time profile and pharmacokinetic parameters of acetaminophen werecalculated by DAS software.Results: The concentration-time curves of acetaminophen in both blood and FrCxextracellular fluid of rats were fitted to a one-compartment open model. The main pharmacokinetic parameters t1/2, Tmax, Cmaxand AUC0-∞were (1.20±0.30) h,(0.58±0.13) h,(129.45±34.08) μg/mL and (361.36±84.69) μg/mL*h, respectively, inblood, while the parameters were (1.95±0.59) h,(1.26±0.22) h,(15.19±3.17)μg/mL and (77.38±22.39) μg/mL*h, respectively, in the FrCx extracellular fluid.Among these parameters, Cmaxand AUC0-∞of acetaminophen in the FrCx extracellularfluid were significantly decreased (P <0.01), while t1/2and Tmaxwere significantlyprolonged (P <0.05or P <0.01), as compared with data in blood.Conclusion:①The pharmacokinetic processes of acetaminophen in blood and FrCxextracellular fluid were fitted to a one-compartment open model in rats.②Comparedwith data in blood, the Cmaxand AUC0-∞of acetaminophen were significantly decreasedin the FrCx extracellular fluid, while t1/2and Tmaxwere significantly prolonged.③Onesimple and feasible studying method with in vivo microdialysis for pharmacokinetics ofdrugs in the target organ (frontal cortex) was established in rats.