Simultaneous PET Imaging of P-Glycoprotein Inhibition in Multiple Tissues in the Pregnant Nonhuman Primate

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 11 C-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 11 C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n 5 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 11 C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC tissue / AUC plasma ) served as a measure of the tissue distribution of 11 C radioactivity. CsA effect on 11 C 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 11 C 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 11 C radioactivity by 276% 6 88% (P , 0.05) and 122% 6 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.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Likewise, fetal penetration of the cardiac glycoside digoxin, the antiviral drug saquinavir, and the chemotherapeutic agent paclitaxel is enhanced in Mdr1a/1b-null mice (Smit et al, 1999). Similar to knockout mice, when pregnant macaques are administered the Pgp inhibitor cyclosporine A, the penetration of radiolabeled verapamil (Pgp substrate) into maternal brain and fetal livers increases (Eyal et al, 2009). Active efflux of potentially toxic chemicals from the fetus to the mother via Pgp may represent a protective mechanism to limit drug-induced birth defects.…”

“…Using positron emission tomography, it has been shown that administration of the Pgp inhibitor cyclosporine A to pregnant macaques increases the penetration of radiolabeled verapamil (Pgp substrate) into brain (Eyal et al, 2009). This imaging modality may be important in screening chemicals for Mdr1a/1b inhibition.…”

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.…”

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

“…11 C]-verapamil (29,36,69,70) and its (R)-enantiomer (39,(71)(72)(73) and the radiolabeled loperamide metabolite, [ 11 C]-dLop (48,74). In addition to these compounds, cytotoxic drugs, such as daunorubicin (43) and paclitaxel (75), have been radiolabelled and evaluated in various tumor models in rodents (Table III).…”