Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate

Background and purpose: Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina. Experimental approach: Mid-gestational (day 75 ± 13, n = 7) and late-gestational (day 150 ± 10, n = 5) age macaques were imaged after administration of a prototypic P-gp substrate, ¹¹C-verapamil (13.7-75.4 MBq·kg ^-1), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg·kg ^-1·h ^-1). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the ¹¹C- radioactivity concentration-time curve in the tissue (AUC _tissue) to that in the maternal plasma (AUC _plasma). Key results: The CsA-induced change in AUC _{fetal liver}/AUC _{maternalplasma} of ¹¹C-radioactivity significantly increased from mid- (35 ± 25%) to late gestation (125 ± 66%). Likewise, the CsA-induced change in AUC _{maternal brain}/AUC _plasma increased from mid- (172 ± 80%) to late gestation (337 ± 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating ¹¹C-verapamil metabolites were significantly affected by gestational age. Conclusions and implications: P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.