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

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

Research output: Contribution to journalArticle

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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 2010
Externally publishedYes

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P-Glycoprotein
Positron-Emission Tomography
Primates
Area Under Curve
Pregnancy
Cyclosporine
Radioactivity
Gestational Age
Mothers
Macaca
Verapamil
Macaca nemestrina
Maternal Exposure
Liver
Brain
Drug-Related Side Effects and Adverse Reactions
Blood-Brain Barrier
Intravenous Infusions
Fetus
Pharmacokinetics

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate. / Chung, F. S.; Eyal, S.; Muzi, M.; Link, Jeanne; Mankoff, D. A.; Kaddoumi, A.; O'Sullivan, F.; Hsiao, P.; Unadkat, Jashvant D.

In: British Journal of Pharmacology, Vol. 159, No. 2, 01.2010, p. 394-404.

Research output: Contribution to journalArticle

Chung, FS, Eyal, S, Muzi, M, Link, J, Mankoff, DA, Kaddoumi, A, O'Sullivan, F, Hsiao, P & Unadkat, JD 2010, 'Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate', British Journal of Pharmacology, vol. 159, no. 2, pp. 394-404. https://doi.org/10.1111/j.1476-5381.2009.00538.x
Chung, F. S. ; Eyal, S. ; Muzi, M. ; Link, Jeanne ; Mankoff, D. A. ; Kaddoumi, A. ; O'Sullivan, F. ; Hsiao, P. ; Unadkat, Jashvant D. / Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate. In: British Journal of Pharmacology. 2010 ; Vol. 159, No. 2. pp. 394-404.
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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.",
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AU - Eyal, S.

AU - Muzi, M.

AU - Link, Jeanne

AU - Mankoff, D. A.

AU - Kaddoumi, A.

AU - O'Sullivan, F.

AU - Hsiao, P.

AU - Unadkat, Jashvant D.

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