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Simultaneous PET Imaging of P-Glycoprotein Inhibition in Multiple Tissues in the Pregnant Nonhuman Primate

¹ Department of Pharmaceutics, University of Washington, Seattle, Washington; ² Division of Nuclear Medicine, University of Washington, Seattle, Washington; ³ University College Cork, Cork, Ireland; and ⁴ Departments of Pharmacy, Obstetrics and Gynecology, University of Washington, Seattle, Washington

View larger version (21K): [in this window] [in a new window]   FIGURE 1.  Schematic of PET protocol. Protocol for 1 animal was modified and shortened.

View larger version (16K): [in this window] [in a new window]   FIGURE 2.  Blood CsA concentration time profiles from time of 11C-verapamil injection (t = 0). Legend indicates animal and CsA dose. Rectangle highlights modest change in CsA blood concentration over 0–9 min, the focus of our data analysis. *Animal was studied for only 25 min.

View larger version (15K): [in this window] [in a new window]   FIGURE 3.  Percentage of 11C radioactivity in plasma before and during CsA infusion show that verapamil is rapidly metabolized in pregnant macaques. At 9 min, CsA did not significantly affect plasma radioactivity of verapamil and D-617/D-717 but decreased radioactivity of polar metabolites. At 40 min, less than 20% of total radioactivity was verapamil with or without CsA. Data are expressed as mean ± SD (n = 4). Data without and with CsA (at given time point) were compared using Mann–Whitney test. *P < 0.05.

View larger version (20K): [in this window] [in a new window]   FIGURE 4.  Plasma (A) and tissue (B–L) 11C radioactivity concentration time profiles in representative animal without () and with () CsA (12 mg/kg/h). With CsA, these profiles show greater distribution of radioactivity into maternal brain (B) and fetal liver (C) but lesser distribution into maternal liver (D). In maternal gallbladder (E), CsA initially increased accumulation of 11C radioactivity but reduced it at later time points. CsA did not change time–concentration profiles of radioactivity in plasma or other tissues.

View larger version (86K): [in this window] [in a new window]   FIGURE 5.  PET images of pregnant M. nemestrina before (A) and during (B) administration of CsA (12 mg/kg/h). PET scans (A and B) are SUV images summed over a period of 1–9 min after 11C-verapamil injection. Images A and B were scaled to the same pixel value. (C) Image produced by pixel-by-pixel subtraction of scan A from scan B. Fetal liver was reporter of 11C radioactivity that crossed placental barrier. Because of P-gp inhibition, CsA significantly increased distribution of 11C radioactivity into maternal brain and fetal liver (yellow to red areas in B and C). In maternal liver, CsA decreased amount of 11C radioactivity (darker area in C). Color scale reflects SUV as shown by thermometer. (D) T2-weighted MR image of the same animal. SUV = standardized uptake value.

View larger version (9K): [in this window] [in a new window]   FIGURE 6.  Effect of CsA on distribution (percentage change in AUCtissue/AUCplasma) of 11C radioactivity into maternal brain and fetal liver was large and significant. In contrast, its effect on distribution of 11C radioactivity into other tissues was insignificant. Data are expressed as mean ± SD (n = 4). *P < 0.05.