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Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes

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Abstract

Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of 99mTc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of 99mTc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, 99mTc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102±31 and 109±16 s, respectively (P=NS). In normal mice and rats, 55%±11% and 55%±6%, respectively, of the maximal sestamibi activity was retained in the liver after 1 h (P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 (ABCB1) gene, 88%±11% of maximal sestamibi activity was retained in the liver after 1 h (P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 (ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs (P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.

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Acknowledgements

We thank Dr. J. Kandimalla for assistance with animal surgery, and our late colleague, Dr. Menes Afriyie, for image analysis. The work was supported in part by NIH grants RO1 DK46952, P30 DK41296, P30 CA13330, and MO1 RR12248, and by grant 3894 from the Long Island Jewish Medical Center.

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Authors and Affiliations

  1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY 10461, USA

    Brigid Joseph, Harmeet Malhi & Sanjeev Gupta

  2. Division of Nuclear Medicine, Long Island Jewish Medical Center, New York, USA

    Kuldeep K. Bhargava & Christopher J. Palestro

  3. Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA

    Michael L. Schilsky

  4. Division of Nuclear Cardiology, MCP-Hahnemann University School of Medicine, Philadephia, USA

    Diwakar Jain

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  1. Brigid Joseph
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Correspondence to Sanjeev Gupta.

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Joseph, B., Bhargava, K.K., Malhi, H. et al. Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes. Eur J Nucl Med Mol Imaging 30, 1024–1031 (2003). https://doi.org/10.1007/s00259-002-1111-z

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