Hepatic technetium Tc 99m-labeled sestamibi elimination rate and ABCB1 (MDR1) genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer

Mark Wong, Scott Evans, Laurent P. Rivory, Janelle M. Hoskins, Graham J. Mann, David Farlow, Christine L. Clarke, Rosemary L. Balleine, Howard Gurney

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 ( 99mTc-MIBI) in patients with cancer and to compare this putative indicator of ABCB1 phenotype with clinical features and common ABCB1 genetic variants. 99mTc-MIBI k H was determined from the time-dependent elimination profile of 99mTc-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. There was a 12-fold variation in 99mTc-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 99mTc-MIBI k H was significantly reduced in patients with SNPs in exons 21 and 26 such that mean 99mTc-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. Hepatic elimination of 99mTc-MIBI is a potential in vivo probe of hepatic ABCB1 activity that is significantly associated with the presence of common SNPs in ABCB1. 99mTc-MIBI hepatic scanning may provide a useful pretreatment indicator of ABCB1-mediated drug clearance in cancer patients.

LanguageEnglish
Pages33-42
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume77
Issue number1
DOIs
Publication statusPublished - Jan 2005
Externally publishedYes

Fingerprint

Technetium Tc 99m Sestamibi
P-Glycoprotein
Single Nucleotide Polymorphism
Genotype
Liver
Exons
Neoplasms
Confidence Intervals
Liver Function Tests
Restriction Fragment Length Polymorphisms
Adenosine Triphosphate
Alleles
Neoplasm Metastasis
Phenotype
Drug Therapy
Polymerase Chain Reaction
Pharmaceutical Preparations
Hepatobiliary Elimination

Cite this

Wong, Mark ; Evans, Scott ; Rivory, Laurent P. ; Hoskins, Janelle M. ; Mann, Graham J. ; Farlow, David ; Clarke, Christine L. ; Balleine, Rosemary L. ; Gurney, Howard. / Hepatic technetium Tc 99m-labeled sestamibi elimination rate and ABCB1 (MDR1) genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer. In: Clinical Pharmacology and Therapeutics. 2005 ; Vol. 77, No. 1. pp. 33-42.
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abstract = "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 ( 99mTc-MIBI) in patients with cancer and to compare this putative indicator of ABCB1 phenotype with clinical features and common ABCB1 genetic variants. 99mTc-MIBI k H was determined from the time-dependent elimination profile of 99mTc-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. There was a 12-fold variation in 99mTc-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 99mTc-MIBI k H was significantly reduced in patients with SNPs in exons 21 and 26 such that mean 99mTc-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. Hepatic elimination of 99mTc-MIBI is a potential in vivo probe of hepatic ABCB1 activity that is significantly associated with the presence of common SNPs in ABCB1. 99mTc-MIBI hepatic scanning may provide a useful pretreatment indicator of ABCB1-mediated drug clearance in cancer patients.",
author = "Mark Wong and Scott Evans and Rivory, {Laurent P.} and Hoskins, {Janelle M.} and Mann, {Graham J.} and David Farlow and Clarke, {Christine L.} and Balleine, {Rosemary L.} and Howard Gurney",
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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. / Wong, Mark; Evans, Scott; Rivory, Laurent P.; Hoskins, Janelle M.; Mann, Graham J.; Farlow, David; Clarke, Christine L.; Balleine, Rosemary L.; Gurney, Howard.

In: Clinical Pharmacology and Therapeutics, Vol. 77, No. 1, 01.2005, p. 33-42.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Evans, Scott

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