Simultaneous PET imaging of P-glycoprotein inhibition in multiple tissues in the pregnant nonhuman primate

Sara Eyal, Francisco S. Chung, Mark Muzi, Jeanne Link, David A. Mankoff, Amal Kaddoumi, Finbarr O'Sullivan, Mary F. Hebert, Jashvant D. Unadkat

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38 Scopus citations

Abstract

Studies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used 11C-verapamil as the prototypic P-gp substrate and cyclosporine A (CsA) as the prototypic inhibitor. Methods: Four pregnant macaques (gestational age, 145-159 d; gestational term, 172 d) were imaged after the intravenous administration of 11C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n = 2 each). The content of verapamil and its metabolites in plasma samples was determined using a rapid solid-phase extraction method. The plasma and tissue time-radioactivity concentration curves of 11C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC tissue/AUCplasma) served as a measure of the tissue distribution of 11C radioactivity. CsA effect on 11C radioactivity distribution was interpreted as P-gp inhibition. The change in the fetal liver AUC ratio served as a reporter of placental P-gp inhibition. Results: CsA effect on tissue distribution of 11C radioactivity (AUC ratios) did not increase with the mean blood concentration of CsA, indicating a near-maximal P-gp inhibition. CsA increased maternal brain and fetal liver distribution of 11C radioactivity by 276% ± 88% (P <0.05) and 122% ± 75% (P <0.05), respectively. Changes in other measured tissues were not statistically significant. Conclusion: These data demonstrate for the first time, to our knowledge, the feasibility of simultaneous, serial, noninvasive imaging of P-gp activity and inhibition in multiple maternal organs and the placenta in the nonhuman primate. Our findings, consistent with previous data in rodents, indicate that the activity of P-gp in the placenta and the blood-brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.

Original languageEnglish (US)
Pages (from-to)798-806
Number of pages9
JournalJournal of Nuclear Medicine
Volume50
Issue number5
DOIs
Publication statusPublished - May 1 2009
Externally publishedYes

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Keywords

  • C-verapamil
  • Blood-brain barrier
  • Cyclosporine A
  • P-glycoprotein
  • Pregnancy

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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