@article {Eyal798, author = {Sara Eyal and Francisco S. Chung and Mark Muzi and Jeanne M. Link and David A. Mankoff and Amal Kaddoumi and Finbarr O{\textquoteright}Sullivan and Mary F. Hebert and Jashvant D. Unadkat}, title = {Simultaneous PET Imaging of P-Glycoprotein Inhibition in Multiple Tissues in the Pregnant Nonhuman Primate}, volume = {50}, number = {5}, pages = {798--806}, year = {2009}, doi = {10.2967/jnumed.108.059360}, publisher = {Society of Nuclear Medicine}, 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{\textendash}159 d; gestational term, 172 d) were imaged after the intravenous administration of 11C-verapamil (30{\textendash}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{\textendash}radioactivity concentration curves of 11C were integrated over 0{\textendash}9 min after each verapamil injection. The tissue or arterial plasma area under the time{\textendash}concentration curve (AUCtissue/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\% {\textpm} 88\% (P \< 0.05) and 122\% {\textpm} 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{\textendash}brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/50/5/798}, eprint = {https://jnm.snmjournals.org/content/50/5/798.full.pdf}, journal = {Journal of Nuclear Medicine} }