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

Abstract

Through PET imaging, our laboratory has studied the dynamic biodistribution of 11C-verapamil, a P-gp substrate, in the non-human 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 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 ± 1.07 μM, vs. BPB IC50, 7.63 ± 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–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.

Role of (Drug) Transporters in Imaging in Health and Disease

“…Similarly, as previously demonstrated by us and others (Sasongko et al, 2005;Hsiao et al, 2008;Eyal et al, 2009Eyal et al, , 2010Muzi et al, 2009;Bauer et al, 2012;Mullauer et al, 2012;Bankstahl et al, 2013;Ke et al, 2013;Deo et al, 2014), when a drug is effluxed out of the brain, its concentration in the brain can be much lower than that in the plasma. This disconnect between tissue and plasma drug concentration will be modulated in the presence of a drug-drug interaction (DDI).…”

“…Such data are best obtained using noninvasive imaging methods (such as PET imaging) to determine drug transport concentrations in various tissues (e.g., brain, fetus, and liver). Such data are available from our laboratory (Hsiao et al, 2008;Eyal et al, 2009Eyal et al, , 2010Muzi et al, 2009;Ke et al, 2013;Deo et al, 2014;He et al, 2014) and others. Therefore, the accuracy of the above proposed IVIVE method can now be tested.…”

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

“…As indicated in preceding sections, the strategy to overcome resistance by inhibiting the activity of efflux pumps, such as P-gp, is also fraught with danger. P-gp is expressed at numerous locations in healthy tissue, and its inhibition will effectively open sanctuary sites (e.g., central nervous system and testes) to cytotoxic anticancer drugs (Leslie et al, 2005;de Vries et al, 2007;Robillard et al, 2012;Ke et al, 2013).…”

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

“…From results of in vitro studies, the drug is known to activate Pgp-coupled ATP-hydrolysis [20]. This drug manifests a spectrum of characteristics, ranging from being a good substrate to a non-substrate for the transporter, which depends on the cell type being evaluated in in vitro cell studies [21][22][23][24][25][26] or host tissue type in in vivo studies [27][28][29]. Although the actual molecular details of these interactions are currently unknown, the drug has been shown to inhibit the ATPase activity of a second drug by competitive, non-competitive and allosteric mechanisms in an in vitro study [30].…”