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

F. S. Chung, S. Eyal, M. Muzi, J. M. Link, D. A. Mankoff, A. Kaddoumi, F. O'Sullivan, P. Hsiao, Jashvant D. Unadkat

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26 Scopus citations

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, 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.

Original languageEnglish (US)
Pages (from-to)394-404
Number of pages11
JournalBritish Journal of Pharmacology
Volume159
Issue number2
DOIs
StatePublished - Jan 1 2010

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Keywords

  • ABCB1 (MDR1, P-glycoprotein)
  • Blood-brain barrier
  • C-verapamil
  • Non-human primates
  • Pregnancy

ASJC Scopus subject areas

  • Pharmacology

Cite this

Chung, F. S., Eyal, S., Muzi, M., Link, J. M., Mankoff, D. A., Kaddoumi, A., O'Sullivan, F., Hsiao, P., & Unadkat, J. D. (2010). Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate. British Journal of Pharmacology, 159(2), 394-404. https://doi.org/10.1111/j.1476-5381.2009.00538.x