Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes.
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 (99m)Tc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of (99m)Tc-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, (99m)Tc-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.
Joseph
Brigid
B
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Bhargava
Kuldeep K
KK
Malhi
Harmeet
H
Schilsky
Michael L
ML
Jain
Diwakar
D
Palestro
Christopher J
CJ
Gupta
Sanjeev
S
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D008099:Liver / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D011877:Radionuclide Imaging; D051381:Rats; D020332:Rats, Inbred LEC; D013379:Substrate Specificity; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D017256:Technetium Tc 99m Sestamibi; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3