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Abstract
Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate
Author: Chung, F. S., Eyal, S., Muzi, M., Link, J. M., Mankoff, D. A., Kaddoumi, A., O'Sullivan, F., Hsiao, P., Unadkat, J. D.
Source: British journal of pharmacology, 159(2), 394-404, 2010
Abstract: 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, (11)C-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 (11)C-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(maternal)(plasma) of (11)C-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 (11)C-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.
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