Park Seonghee, Sinko Patrick J
Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Rd., Piscataway, NJ 08854, USA.
J Pharmacol Exp Ther. 2005 Mar;312(3):1249-56. doi: 10.1124/jpet.104.076216. Epub 2004 Nov 4.
Efflux transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (Mrps) and their contributions to saquinavir (SQV) brain uptake were characterized. Cerebral flow rate was estimated from diazepam uptake and brain vascular volume was assessed using inulin. Mice brains were perfused with buffer containing SQV alone or coperfused with different concentrations of GF120918, a P-gp inhibitor or MK571, a specific Mrp family inhibitor. Inulin, a nonabsorbable marker, was also coperfused in all studies to assess whether the inhibitors altered the physical integrity of the blood-brain barrier (BBB). The estimated cerebral flow rate using diazepam was 250 ml.100g(-1.)min(-1). The brain vascular volume, estimated using inulin, was almost constant (0.94 +/- 0.03 ml.100 g(-1), n = 12) during the perfusion study. SQV uptake kinetics was linear during the sampling period. Inclusion of 10 muM GF120918 in the perfusate resulted in a more than 7-fold increase in the brain distributional volume (i.e., uptake) of SQV. Inclusion of 100 muM MK571 in the perfusate increased SQV apparent brain uptake by more than 4.4-fold, suggesting, for the first time, that Mrp transporters may play an important role in the brain uptake and retention of SQV. Neither GF120918 nor MK571 altered the integrity of the BBB during the time course of the study. Although the current results reaffirm that SQV is a P-gp substrate, this is the first report implicating the Mrp transporter family in the limited brain uptake and retention of SQV in vivo in mice.
对诸如P-糖蛋白（P-gp）和多药耐药相关蛋白（Mrps）等外排转运体及其对沙奎那韦（SQV）脑摄取的贡献进行了表征。通过地西泮摄取估算脑血流量，并使用菊粉评估脑血管容积。用仅含SQV的缓冲液灌注小鼠脑，或与不同浓度的P-gp抑制剂GF120918或特定Mrp家族抑制剂MK571共同灌注。在所有研究中还共同灌注菊粉（一种不可吸收的标记物），以评估抑制剂是否改变血脑屏障（BBB）的物理完整性。用地西泮估算的脑血流量为250 ml·100g⁻¹·min⁻¹。在灌注研究期间，用菊粉估算的脑血管容积几乎恒定（0.94±0.03 ml·100 g⁻¹，n = 12）。在采样期间，SQV摄取动力学呈线性。灌注液中加入10 μM GF120918导致SQV的脑分布容积（即摄取）增加了7倍以上。灌注液中加入100 μM MK571使SQV的表观脑摄取增加了4.4倍以上，首次表明Mrp转运体可能在SQV的脑摄取和潴留中起重要作用。在研究过程中，GF120918和MK571均未改变BBB的完整性。尽管目前的结果再次证实SQV是P-gp的底物，但这是首次报道Mrp转运体家族在小鼠体内对SQV有限的脑摄取和潴留中的作用。
