Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA.
J Nucl Med. 2013 Mar;54(3):437-46. doi: 10.2967/jnumed.112.111732. Epub 2013 Jan 28.
Through PET imaging, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling.
Thirteen pregnant macaques (gestational age, 71-159 d; term, ∼172 d) underwent PET imaging with (11)C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic (11)C-verapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model.
The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of (11)C-radioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K1) approximated tissue blood flow (Q); that is, extraction ratio (K1/Q) was approximately 1, indicating that in the absence of P-gp function, the distribution of (11)C-verapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC50], 5.67 ± 1.07 μM, vs. BPB IC50, 7.63 ± 3.16 μM).
We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp-based drug interactions at the human BBB and BPB can be clinically significant, particularly for those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments.
通过 PET 成像，我们的实验室研究了非人类灵长类动物猕猴中 P-糖蛋白（P-gp）底物（11）C-verapamil 的动态生物分布。为了更深入地了解维拉帕米通过血脑屏障（BBB）和血胎盘屏障（BPB）的转运动力学，我们通过房室模型分析了这些动态生物分布数据。
13 只怀孕的猕猴（孕龄 71-159 天；足月约 172 天）在环孢素 A（CsA，一种 P-糖蛋白 [P-gp] 抑制剂）输注（6、12 或 24mg/kg/h）前后进行（11）C-verapamil PET 成像。通过 1 或 2 组织房室模型评估动态（11）C-verapamil 脑或胎肝（胎盘 P-gp 功能的报告者）活性。
1 组织房室模型最好地解释了观察到的（11）C 放射性脑和胎肝分布。当 P-gp 完全被抑制时，脑和胎肝分布清除率（K1）接近组织血流（Q）；即，提取比（K1/Q）约为 1，表明在没有 P-gp 功能的情况下，（11）C-verapamil 放射性在这些隔室中的分布受到血流限制。CsA 抑制 P-gp 的效力与组织无关（母体 BBB 半抑制浓度 [IC50]，5.67±1.07μM，vs. BPB IC50，7.63±3.16μM）。
我们提出，在故意或无意的 P-gp 抑制下，亲脂性药物（如维拉帕米）在人脑（或胎儿）中的分布增加的上限将受到组织血流的限制。这一发现为当仅通过 PET 获得药物穿过这些屏障的基线分布（即在没有 P-gp 抑制的情况下）时，预测 BBB 和 BPB 处基于 P-gp 的药物相互作用的幅度提供了一种方法。我们的数据表明，人 BBB 和 BPB 处基于 P-gp 的药物相互作用可能具有临床意义，特别是对于那些 P-gp 在将药物排除在这些特权隔室中起重要作用的 P-gp 底物药物。
