Radiopharmaceuticals for hepatobiliary imaging

Chervu, L. Rao; Nunn, Adrian D.; Loberg, Michael D.

doi:10.1016/s0001-2998(82)80025-1

Cited by 83 publications

(23 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides proving the high in vivo stability of these chelates, this study also illustrated how the biodistribution and excretion properties of complexes injected into the blood stream are influenced by their molecular size, molecular weight, charge and hydrophilicity [12,13]. Other examples are found in the literature of very stable complexes of 67 Ga with triazamacrocycles containing different pendant arms, conferring to some of them different biodistribution and clearance pathways [14][15][16].…”

Section: Introductionmentioning

confidence: 56%

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Prata¹,

Santos²,

Geraldes³

et al. 2000

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

The solution chemistry and structure of the complex of the triazamacrocyclic ligand NOTP (1,4,7-triazacyclononane-1,4,7-tris(methylenephosphonate)) with Ga3+ in D2O have been investigated by 1H, 71Ga and 31P NMR spectroscopy. These NMR results show the presence of a 1:1 Ga(NOTP)3- complex, with a highly symmetrical, pseudo-octahedral geometry, possibly with a C3 axis. The 1H spectrum shows that the triazamacrocyclic chelate ring is very rigid, with all the ring protons non-equivalent. The complex is stable in aqueous solution in a wide pH range. Its high thermodynamic stability agrees well with previous results from biodistribution and gamma imaging studies in Wistar rats with 67Ga3+ chelates of triaza macrocyclic ligands, which showed that the neutral chelates 67Ga(NOTA) (where NOTA is 1,4,7-triazacyclononane-1,4,7-triacetate) and 67Ga(NOTPME) (where NOTPME is 1,4,7-triazacyclononane-1,4,7-tris(methylenephosphonate monoethylester)) have similar in vivo behaviour, with high stability and rapid renal excretion, but the high negatively charged 67Ga(NOTP)3- has a considerably slower kidney uptake and elimination.

show abstract

Section: Introductionmentioning

confidence: 56%

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Prata¹,

Santos²,

Geraldes³

et al. 2000

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

show abstract

“…Previously published data involving administration of 99m Tc-mebrofenin (and other iminodiacetic acid derivatives) in humans or animals focused on the time-activity data in blood and liver up to 60 min. 14,[31][32][33][34] A two-compartment model representing blood and liver reasonably approximated 0-60 min time-activity data in these studies. 31,32 However, extending the time course of blood and liver observations to 180 min clearly demonstrates more complex pharmacokinetic behavior; the statistically significant, twofold increase in 99m Tc-mebrofenin systemic exposure without accompanying changes in hepatic exposure or biliary recovery observed following ritonavir administration (2 × 300 mg) is not consistent with a two-compartment model.…”

Section: Discussionmentioning

confidence: 82%

“…14,[31][32][33][34] A two-compartment model representing blood and liver reasonably approximated 0-60 min time-activity data in these studies. 31,32 However, extending the time course of blood and liver observations to 180 min clearly demonstrates more complex pharmacokinetic behavior; the statistically significant, twofold increase in 99m Tc-mebrofenin systemic exposure without accompanying changes in hepatic exposure or biliary recovery observed following ritonavir administration (2 × 300 mg) is not consistent with a two-compartment model. 99m Tc-mebrofenin did not accumulate in extrahepatic tissues within the γ camera fieldof-view, yet the liver-to-blood ratio and incomplete recovery of total activity in urine and bile suggested an extrahepatic component to 99m Tc-mebrofenin disposition.…”

Section: Discussionmentioning

confidence: 82%

Effect of Ritonavir on ^99mTechnetium–Mebrofenin Disposition in Humans: A Semi‐PBPK Modeling and In Vitro Approach to Predict Transporter‐Mediated DDIs

Pfeifer

Goss

Swift

et al. 2013

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

A semiphysiologically based pharmacokinetic (semi-PBPK) model was developed to describe a unique blood, liver, and bile clinical data set for the hepatobiliary imaging agent 99mTechnetium–mebrofenin (99mTc–mebrofenin), and to simulate sites/mechanisms of a 99mTc–mebrofenin–ritonavir drug–drug interaction (DDI). The transport inhibitor ritonavir (multiple-dose: 2 × 300 mg) significantly increased systemic 99mTc–mebrofenin exposure as compared with control (4,464 ± 1,861 vs. 1,970 ± 311 nCi min/ml; mean ± SD), without affecting overall hepatic exposure or biliary recovery. A novel extrahepatic distribution compartment was required to characterize 99mTc–mebrofenin disposition. Ritonavir inhibited 99mTc–mebrofenin accumulation in human sandwich-cultured hepatocytes (SCH) (half maximal inhibitory concentration (IC50) = 3.46 ± 1.53 µmol/l). Despite ritonavir accumulation in hepatocytes, intracellular binding was extensive (97. 6%), which limited interactions with multidrug resistance protein 2 (MRP2)-mediated biliary excretion. These in vitro data supported conclusions from modeling/simulation that ritonavir inhibited 99mTc–mebrofenin hepatic uptake, but not biliary excretion, at clinically relevant concentrations. This integrated approach, utilizing modeling, clinical, and in vitro data, emphasizes the importance of hepatic and extrahepatic distribution, assessment of inhibitory potential in relevant in vitro systems, and intracellular unbound concentrations to assess transporter-mediated hepatic DDIs.

show abstract

“…Before initiation of UDCA therapy, conventional liver function tests and determination of fasting serum bile acid levels were carried out. Each patient also underwent hepatobiliary scintigraphy with a new-generation technetium-labeled iminodiacetic agent (22). Standard liver function tests, fasting serum bile acid level and biliary bile acid composition tests and hepatobiliary scanning were performed again after 10 to 12 mo of UDCA therapy.…”

Section: Methodsmentioning

confidence: 99%

Scintigraphic Documentation of An Improvement in Hepatobiliary Excretory Function After Treatment With Ursodeoxycholic Acid in Patients With Cystic Fibrosis and Associated Liver Disease

et al. 1992

View full text Add to dashboard Cite

We have previously documented that ursodeoxycholic acid exerts a beneficial effect on liver function and bile acid metabolism in patients with cystic fibrosis. We hypothesized that the mechanism of action may be related in part to the choleretic properties of the administered bile acid. We therefore compared hepatobiliary scintigraphic images obtained before and 1 yr after initiation of ursodeoxycholic acid therapy to document an improvement in bile flow in 13 patients with cystic fibrosis and hepatobiliary involvement. Before therapy, hepatobiliary scintigraphy documented biliary stasis with retention of the isotope in intrahepatic and extrahepatic bile ducts in nine patients; during therapy, duct dilatation decreased substantially in eight patients, with decreased intrahepatic retention and more rapid biliary outflow of the tracer. The time of appearance of isotope in the intestine decreased (from a mean of 36.9 +/- 17.8 min to 18.8 +/- 9.0 min; p less than 0.01) in all patients in whom it had been abnormal, and the half-time of hepatic washout decreased from a mean of 35 +/- 20.7 min to 26 +/- 15.6 min (p less than 0.05). During ursodeoxycholic acid administration enrichment of bile was achieved, with the mean ursodeoxycholic acid percent composition increasing from 5.8% +/- 2.9% to 35.7% +/- 8.5%. Ursodeoxycholic acid became the predominant bile acid in serum. Liver function improved in all 10 of the patients with abnormal values at baseline. We conclude that hepatobiliary scintigraphy is of value in monitoring the therapeutic responses of cystic fibrosis patients with liver disease to ursodeoxycholic acid therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Radiopharmaceuticals for hepatobiliary imaging

Cited by 83 publications

References 39 publications

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Effect of Ritonavir on ^99mTechnetium–Mebrofenin Disposition in Humans: A Semi‐PBPK Modeling and In Vitro Approach to Predict Transporter‐Mediated DDIs

Scintigraphic Documentation of An Improvement in Hepatobiliary Excretory Function After Treatment With Ursodeoxycholic Acid in Patients With Cystic Fibrosis and Associated Liver Disease

Contact Info

Product

Resources

About

Radiopharmaceuticals for hepatobiliary imaging

Cited by 83 publications

References 39 publications

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Structural and in vivo studies of metal chelates of Ga(III) relevant to biomedical imaging

Effect of Ritonavir on 99mTechnetium–Mebrofenin Disposition in Humans: A Semi‐PBPK Modeling and In Vitro Approach to Predict Transporter‐Mediated DDIs

Scintigraphic Documentation of An Improvement in Hepatobiliary Excretory Function After Treatment With Ursodeoxycholic Acid in Patients With Cystic Fibrosis and Associated Liver Disease

Contact Info

Product

Resources

About

Effect of Ritonavir on ^99mTechnetium–Mebrofenin Disposition in Humans: A Semi‐PBPK Modeling and In Vitro Approach to Predict Transporter‐Mediated DDIs