@article {Ke437, author = {Alice Ban Ke and Sara Eyal and Francisco S. Chung and Jeanne M. Link and David A. Mankoff and Mark Muzi and Jashvant D. Unadkat}, title = {Modeling Cyclosporine A Inhibition of the Distribution of a P-Glycoprotein PET Ligand, 11C-Verapamil, into the Maternal Brain and Fetal Liver of the Pregnant Nonhuman Primate: Impact of Tissue Blood Flow and Site of Inhibition}, volume = {54}, number = {3}, pages = {437--446}, year = {2013}, doi = {10.2967/jnumed.112.111732}, publisher = {Society of Nuclear Medicine}, abstract = {Through PET imaging, our laboratory has studied the dynamic biodistribution of 11C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood{\textendash}brain barrier (BBB) and the blood{\textendash}placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling. Methods: Thirteen pregnant macaques (gestational age, 71{\textendash}159 d; term, \~{}172 d) underwent PET imaging with 11C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic 11C-verapamil 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 11C-radioactivity. 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 11C-verapamil 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 {\textpm} 1.07 μM, vs. BPB IC50, 7.63 {\textpm} 3.16 μM). 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{\textendash}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{\textendash}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.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/54/3/437}, eprint = {https://jnm.snmjournals.org/content/54/3/437.full.pdf}, journal = {Journal of Nuclear Medicine} }