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Hepatic Technetium Tc 99m–labeled Sestamibi Elimination Rate and ABCB1 ( MDR1 ) Genotype as Indicators of ABCB1 (P–glycoprotein) Activity in Patients with Cancer
Author(s) -
Wong Mark,
Evans Scott,
Rivory Laurent P.,
Hoskins Janelle M.,
Mann Graham J.,
Farlow David,
Clarke Christine L.,
Balleine Rosemary L.,
Gurney Howard
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.09.002
Subject(s) - single nucleotide polymorphism , genotype , medicine , gastroenterology , p glycoprotein , metastasis , confidence interval , cancer , biology , endocrinology , gene , genetics , drug resistance , multiple drug resistance
Background and Objective The adenosine triphosphate‐binding cassette transporter ABCB1 (P‐glycoprotein) mediates terminal excretion of many chemotherapeutic agents, and variable ABCB1 activity may be an important contributor to interpatient variability in the clearance of chemotherapeutic agents. Our objective was to determine the elimination constant (k H ) for hepatic elimination of technetium Tc 99m‐labeled sestamibi ( 99m Tc‐MIBI) in patients with cancer and to compare this putative indicator of ABCB1 phenotype with clinical features and common ABCB1 genetic variants. Methods 99m Tc‐MIBI k H was determined from the time‐dependent elimination profile of 99m Tc‐MIBI over a 90‐minute hepatic scanning period in 66 patients with cancer. Single nucleotide polymorphisms (SNPs) in ABCB1 exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) were documented by polymerase chain reaction‐restriction fragment length polymorphism analysis. Results : There was a 12‐fold variation in 99m Tc‐MIBI k H across the cohort, which was not correlated with sex, age, conventional liver function test results, previous chemotherapy treatment, or history of liver metastasis. Mean 99m Tc‐MIBI k H was significantly reduced in patients with SNPs in exons 21 and 26 such that mean 99m Tc‐MIBI k H was 1.90 times (95% confidence interval, 1.14–2.66; P = .02) and 2.21 times (95% confidence interval, 1.47–2.97; P < .01) higher in subjects homozygous for the wild‐type alleles than in those homozygous for these SNPs, respectively. Conclusion Hepatic elimination of 99m Tc‐MIBI is a potential in vivo probe of hepatic ABCB1 activity that is significantly associated with the presence of common SNPs in ABCB1 . 99m Tc‐MIBI hepatic scanning may provide a useful pretreatment indicator of ABCB1‐mediated drug clearance in cancer patients. Clinical Pharmacology & Therapeutics (2005) 77 , 33–42; doi: 10.1016/j.clpt.2004.09.002