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.