Modeling cyclosporine a inhibition of the distribution of a P-glycoprotein PET ligand, 11-Cverapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: Impact of tissue blood flow and site of inhibition

Alice Ban Ke, Sara Eyal, Francisco S. Chung, Jeanne M. Link, David A. Mankoff, Mark Muzi, Jashvant D. Unadkat

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Through PET imaging, our laboratory has studied the dynamic biodistribution of 14-Cverapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling. Methods: Thirteen pregnant macaques (gestational age, 71-159 d; term,∼172 d) underwent PET imaging with 14-Cverapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic 14-Cverapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model. Results: The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of 14-Cradioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K1) approximated tissue blood flow (Q); that is, extraction ratio (K1/Q) was approximately 1, indicating that in the absence of P-gp function, the distribution of 11-Cverapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC50], 5.67 ± 1.07 mM, vs. BPB IC50, 7.63 ± 3.16 mM). Conclusion: We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp- based drug interactions at the human BBB and BPB can be clinically significant, particularly for those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments. COPYRIGHT

Original languageEnglish (US)
Pages (from-to)437-446
Number of pages10
JournalJournal of Nuclear Medicine
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2013

Keywords

  • Blood-brain barrier
  • Blood-placenta barrier
  • P-glycoprotein
  • PET imaging

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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