Rapid solid-phase extraction method to quantify [11C]-verapamil, and its [11C]-metabolites, in human and macaque plasma

Unadkat, Jashvant D.; Chung, Francisco; Sasongko, Lucy; Whittington, Dale; Eyal, Sara; Mankoff, David A.; Collier, Ann C.; Muzi, Mark; Link, Jeanne

doi:10.1016/j.nucmedbio.2008.08.001

Cited by 13 publications

(11 citation statements)

References 19 publications

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“…Blood and plasma radioactivity from 15 O-water, 11 C-verapamil, and 11 C-CO substudies was measured by a γ-counter (Cobra Counter; Packard Corp.). Plasma 11 C-verapamil and metabolite concentrations were determined by solid-phase extraction/HPLC analysis as previously described (13). …”

Section: Methodsmentioning

confidence: 99%

“…Briefly, metabolite assays of plasma after 11 C-verapamil administration resulted in 3 fractions: unchanged verapamil, D617/D717 (formed by dealkylation, henceforth referred to as D617), and other metabolites (formed by N -demethylation, referred to as polar metabolites) (13). An exponential function was fitted to these me-tabolite analysis data to derive the fraction of verapamil, D617, and polar metabolites in arterial plasma (Supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

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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

Eyal

Chung

et al. 2013

J Nucl Med

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Eyal

Chung

et al. 2013

J Nucl Med

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“…The amount of radioactive verapamil and its metabolites in the plasma was determined after solid-phase extraction (SPE) and HPLC, as previously described (5, 21). …”

Section: Methodsmentioning

confidence: 99%

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

Eyal¹,

Chung²,

Muzi³

et al. 2009

J Nucl Med

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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.

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“…SPE is unequivocally the leading sample preparation method used in routine bio-analytical laboratories and also has been applied for metabolite analysis of PET radioligands in plasma [10][11][12][13][14][15]. Although conventional SPE offers several advantages, it has some limitations.…”

Section: Introductionmentioning

confidence: 99%

A simplified radiometabolite analysis procedure for PET radioligands using a solid phase extraction with micellar medium

Nakao

Halldin

2013

Nuclear Medicine and Biology

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Rapid solid-phase extraction method to quantify [11C]-verapamil, and its [11C]-metabolites, in human and macaque plasma

Cited by 13 publications

References 19 publications

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

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

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

A simplified radiometabolite analysis procedure for PET radioligands using a solid phase extraction with micellar medium

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Rapid solid-phase extraction method to quantify [11C]-verapamil, and its [11C]-metabolites, in human and macaque plasma

Cited by 13 publications

References 19 publications

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

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

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

A simplified radiometabolite analysis procedure for PET radioligands using a solid phase extraction with micellar medium

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Product

Resources

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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

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