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 (AUCbrain) and in plasma (AUCplasma). [11C]dLop brain uptake was described by AUCR = AUCbrain/AUCplasma.
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.