The Impact of a Heterozygous SLCO1B3 Null Variant on the Indocyanine Green Retention Test

Anzai, Kazuya; Tsuruya, Kota; Morimachi, Masashi; Arase, Yoshitaka; Hirose, Shunji; Hirabayashi, Kenichi; Adachi, Yukihiko; Kagawa, Tatehiro

doi:10.1016/j.xphs.2020.06.020

Cited by 6 publications

(23 citation statements)

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“…The incidence of ICG excretory defect is 0.007% in the Japanese population (Masuoka et al, 2020). Anzai et al emphasized the importance of investigating the effect of the SLCO1B3 genotype on ICG clearance in cirrhotic patients in the future (Anzai et al, 2020). Within this work, this important investigation could be performed in silico (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…C: Dependency on transport protein amount (OATP1B3). Clinical data from Anzai et al (Anzai et al, 2020), Namihisa et al (Namihisa et al, 1981), andKagawa et al (Kagawa et al, 2017). Heterozygote null variants with 0.5 activity, homozygote null variants with 0.0 activity.…”

Section: Frontiers 17mentioning

confidence: 99%

“…Two proteins on the sinusoidal membrane are mainly responsible for the hepatic uptake of ICG in humans, the organic anion transporting polypeptide 1B3 (OATP1B3, gene symbol: SLCO1B3) and the Na + -taurocholate cotransporting polypeptide (NTCP) (de Graaf et al, 2011;Kagawa et al, 2017). OATP1B3 is the major transporter for hepatic ICG uptake and subjects with a homozygous SLCO1B3 null allele show markedly impaired ICG clearance (Anzai et al, 2020).…”

Section: Transport Protein (Oatp1b3)mentioning

confidence: 99%

“…Model predictions were validated using various clinical data sets from healthy controls and subjects with mild, moderate and severe cirrhosis corresponding to Child-Turcotte-Pugh (CTP) classes A, B, and C, respectively (see Fig. 2: ICG-clearance, ICG-PDR, ICG-R15, and ICG-thalf depending on hepatic blood flow (Grundmann et al, 1992;Møller et al, 1998Møller et al, , 2019Pind et al, 2016;Skak and Keiding, 1987); ICG-clearance, ICG-R15 and ICG-t 1/2 depending on cardiac output (Grundmann et al, 1992;Pind et al, 2016); ICG-PDR and ICG-R15 depending on OATP1B3 (Anzai et al, 2020;Kagawa et al, 2017;Namihisa et al, 1981); ICG-clearance, ICG-PDR, and ICG-R15 depending on liver volume (Haimerl et al, 2016;Hashimoto and Watanabe, 2000;Roberts et al, 1976); ICG-clearance and ICG-PDR depending on body weight (Haimerl et al, 2016;Huet and Villeneuve, 1983). The model predictions show very good agreement with the validation data.…”

Section: Validation Of Physiological Factorsmentioning

confidence: 99%

“…In summary, model predictions for the effect of hepatic blood flow, cardiac output, OATP1B3 level, liver volume, body weight and bilirubin on ICG parameters could be validated with a large set of studies in healthy controls and various degrees of cirrhosis spanning almost 60 years of clinical research (Anzai et al, 2020;Branch et al, 1976;Caesar et al, 1961;D'Onofrio et al, 2014;Gadano et al, 1997;Grundmann et al, 1992;Haimerl et al, 2016;Hashimoto and Watanabe, 2000;Huet and Lelorier, 1980;Huet and Villeneuve, 1983;Kagawa et al, 2017;Kanstrup and Winkler, 1987;Kawasaki et al, 1988;Leevy et al, 1962Leevy et al, , 1967Møller et al, 1998Møller et al, , 2019Namihisa et al, 1981;Pind et al, 2016;Roberts et al, 1976;Skak and Keiding, 1987).…”

Section: Variability Of Icg Liver Function Testsmentioning

confidence: 99%

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Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests

Köller

Grzegorzewski

König

2021

Preprint

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Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move towards an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a large in silico cohort of n=100000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step towards individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.

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Section: Discussionmentioning

confidence: 99%

Section: Frontiers 17mentioning

confidence: 99%

Section: Transport Protein (Oatp1b3)mentioning

confidence: 99%

Section: Validation Of Physiological Factorsmentioning

confidence: 99%

Section: Variability Of Icg Liver Function Testsmentioning

confidence: 99%

See 3 more Smart Citations

Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests

Köller

Grzegorzewski

König

2021

Preprint

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Preoperative indocyanine green (ICG) clearance test: Can we really trust it to predict post hepatectomy liver failure? A systematic review of the literature and meta-analysis of diagnostic test accuracy

Granieri

Bracchetti

Kersik

et al. 2022

Photodiagnosis and Photodynamic Therapy

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Nontoxic Tumor-Targeting Optical Agents for Intraoperative Breast Tumor Imaging

et al. 2022

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Precise identification of the tumor margins during breast-conserving surgery (BCS) remains a challenge given the lack of visual discrepancy between malignant and surrounding normal tissues. Therefore, we developed a fluorescent imaging agent, ICG-p28, for intraoperative imaging guidance to better aid surgeons in achieving negative margins in BCS. Here, we determined the pharmacokinetics (PK), biodistribution, and preclinical toxicity of ICG-p28. The PK and biodistribution of ICG-p28 indicated rapid tissue uptake and localization at tumor lesions. There were no doserelated effect and no significant toxicity in any of the breast cancer and normal cell lines tested. Furthermore, ICG-p28 was evaluated in clinically relevant settings with transgenic mice that spontaneously developed invasive mammary tumors. Intraoperative imaging with ICG-p28 showed a significant reduction in the tumor recurrence rate. This simple, nontoxic, and cost-effective method can offer a new approach that enables surgeons to intraoperatively identify tumor margins and potentially improves overall outcomes by reducing recurrence rates.

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The Impact of a Heterozygous SLCO1B3 Null Variant on the Indocyanine Green Retention Test

Cited by 6 publications

References 8 publications

Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests

Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests

Preoperative indocyanine green (ICG) clearance test: Can we really trust it to predict post hepatectomy liver failure? A systematic review of the literature and meta-analysis of diagnostic test accuracy

Nontoxic Tumor-Targeting Optical Agents for Intraoperative Breast Tumor Imaging

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