Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [¹¹C]-N-desmethyl-loperamide PET study in nonhuman primates

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• 作者：Annelaure Damont ; Sé ; bastien Goutal ; Sylvain Auvity ; Hé ; ric Valette ; Bertrand Kuhnast ; Wadad Saba ; Nicolas Tournier ; ^{nicolas.tournier@cea.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Drug-drug interaction ; Stress-test ; BBB ; Positron emission tomography ; Radiochemistry
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：25 August 2016
• 年：2016
• 卷：91
• 期：Complete
• 页码：98-104
• 全文大小：553 K

文摘

Cyclosporin A (CsA) and dipyridamole (DPy) are potent inhibitors of the P-glycoprotein (P-gp; ABCB1) in vitro. Their efficacy at inhibiting P-gp at the blood-brain barrier (BBB) is difficult to predict. Efficient and readily available (i.e. marketed) P-gp inhibitors are needed as probes to investigate the role of P-gp at the human BBB. In this study, the P-gp inhibition potency at the BBB of therapeutic doses of CsA or DPy was evaluated in baboons using Positron Emission Tomography (PET) imaging with [¹¹C]-N-desmethyl-loperamide ([¹¹C]dLop), a radiolabeled P-gp substrate.

The preparation of dLop as authentic standard and [¹¹C]dLop as radiotracer were revisited so as to improve their production yields. [¹¹C]dLop PET imaging was performed in the absence (n = 3, baseline condition) and the presence of CsA (15 mg/kg/h i.v., n = 3). Three animals were injected with i.v. DPy at either 0.56 or 0.96 or 2 mg/kg (n = 1), corresponding to the usual, maximal and twice the maximal dose in patients, respectively, administered immediately before PET. [¹¹C]dLop brain kinetics as well as [¹¹C]dLop kinetics and radiometabolites in arterial plasma were measured to calculate [¹¹C]dLop area-under the time-activity curve from 10 to 30 min in the brain (AUC_brain) and in plasma (AUC_plasma). [¹¹C]dLop brain uptake was described by AUCR = AUC_brain/AUC_plasma.

CsA as well as DPy did not measurably influence [¹¹C]dLop plasma kinetics and metabolism. Baseline AUCR (0.85 ± 0.29) was significantly enhanced in the presence of CsA (AUCR = 10.8 ± 3.6). Injection of pharmacologic dose of DPy did not enhance [¹¹C]dLop brain distribution with AUCR being 1.2, 0.9 and 1.1 after administration of 0.56, 0.96 and 2 mg/kg DPy doses, respectively.

We used [¹¹C]dLop PET imaging in baboons, a relevant in vivo model of P-gp function at the BBB, to show the P-gp inhibition potency of therapeutic dose CsA. Despite in vitro P-gp inhibition potency, usual doses DPy are not likely to inhibit P-gp function at the BBB.