Gd-BOPTA Transport Into Rat Hepatocytes: Pharmacokinetic Analysis of Dynamic Magnetic Resonance Images Using a Hollow-Fiber Bioreactor

Planchamp, Corinne; Gex‐Fabry, Marianne; Dornier, Christophe; Quadri, Rafael; Reist, Marianne; Ivancevic, Marko K.; Vallée, Jean‐Paul; Pochon, Sibylle; Terrier, François; Balant, L; Stieger, Bruno; Meier, Peter J.; Pastor, Catherine M.

doi:10.1097/01.rli.0000129156.16054.30

Cited by 27 publications

(22 citation statements)

References 47 publications

(58 reference statements)

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“…In a similar experimental model, we previously showed by hepatic MRI that BSP totally abolishes the signal intensity enhancement induced by the coperfusion of BOPTA and BSP (Pastor et al, 2003). In isolated hepatocytes, we confirmed the cellular entry of BOPTA through a membrane transporter that is saturable at high substrate concentrations with a K m of 270 Ϯ 111 M and a V max value of 6.62 Ϯ 1.38 SI units at 30 min (Planchamp et al, 2004). Three Oatps have been described in rat livers: Oatp 1 , Oatp 2 , and Oapt 4 (Hagenbuch and Meier, 2003).…”

Section: Organic Anion Transport Within Hepatocytes Discussionsupporting

confidence: 63%

Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes

Planchamp¹,

Hadengue²,

Stieger³

et al. 2007

Mol Pharmacol

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We hypothesized that the function of both sinusoidal and canalicular transporters importantly controls the concentrations of organic anions within normal hepatocytes. Consequently, we investigated how acute transport regulation of the sinusoidal organic anion transporting polypeptides (Oatps) and the canalicular multidrug resistance associated protein 2 (Mrp 2 ) determines the hepatic concentrations of the organic anion gadolinium benzyloxypropionictetraacetate (BOPTA) in rat livers. Livers were perfused with labeled BOPTA in different experimental settings that modify the function of Oatps and Mrp 2 through the protein kinase C (PKC) pathway. Intrahepatic concentrations were continuously measured with a gamma probe placed above rat livers. Labeled BOPTA was also measured in perfusate and bile. We showed that when the function of Oatps and Mrp 2 is modified in such a way that BOPTA entry and exit are similarly decreased, concentrations of organic anions within hepatocytes remain unaltered. When exit through Mrp 2 is abolished, hepatic concentrations are high if entry through Oatps is only slightly decreased (livers without Mrp 2 expression) or low if BOPTA uptake is more importantly decreased (livers perfused with a PKC activator). These results highlight that the function of both sinusoidal and canalicular transporters is important to determine the concentration of organic anions within hepatocytes.

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Section: Organic Anion Transport Within Hepatocytes Discussionsupporting

confidence: 63%

Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes

Planchamp¹,

Hadengue²,

Stieger³

et al. 2007

Mol Pharmacol

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“…In a hollow-fiber bioreactor containing freshly isolated rat hepatocytes, we showed that the transport of Gd-BOPTA into hepatocytes can be successfully described by compartmental analysis of the MR signal intensity recorded over time and supports the hypothesis of a transportermediated uptake (Planchamp et al, 2004a, b).…”

Section: Introductionsupporting

confidence: 70%

Direct evidence of the temperature dependence of Gd-BOPTA transport in the intact rat liver

Planchamp¹,

Beyer²,

Slosman³

et al. 2005

Applied Radiation and Isotopes

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The aim was to study the influence of temperature on the transport of the hepatobiliary contrast agent Gadobenate dimeglumine (Gd-BOPTA). Rat livers were isolated and perfused with Gd-BOPTA at 12, 25, 30, 36 and 38 1C. After the perfusion period, biopsies were collected and the MR signal intensity was measured. Uptake and biliary excretion were quantified with radiolabeled Gd-BOPTA. MR signal intensity decreased with temperature of perfusion. This phenomenon was appropriately quantified with 153 Gd and 153 Sm labeling, in contrast to 67 Ga. r

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“…Moreover, we also demonstrated that the transport of Gd-BOPTA into isolated rat hepatocytes is saturable with a K m ϭ 0.3 mM. 3 In the literature, 3 transporters (Oatp1, Oatp2, and Oatp4) have been described on the sinusoidal (or plasmatic) membrane of rat hepatocytes, but the exact isoform responsible for Gd-BOPTA uptake is unknown. Following intracellular transport, Gd-BOPTA exits into bile through the ATP-dependent multidrug resistance-associated protein 2 (Mrp2, Abcc2).…”

mentioning

confidence: 99%

Magnetic Resonance Imaging With Hepatospecific Contrast Agents in Cirrhotic Rat Livers

Planchamp¹,

Montet²,

Frossard³

et al. 2005

Investigative Radiology

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Objective: During biliary cirrhosis in rats, organic anion-transporting peptides (Oatps) and ATP-dependent multidrug resistance-associated protein 2 (Mrp2) that are likely to transport the contrast agent Gd-BOPTA through hepatocytes are down-regulated. However, the consequences of such down-regulation on the signal intensity (SI) enhancement are unknown. Consequently, the aim of our study was to measure the hepatic SI enhancement during Gd-BOPTA perfusion as well as the Oatp and Mrp2 expression in normal and cirrhotic livers. Materials and Methods:The hepatic SI enhancement during Gd-BOPTA perfusion was measured in livers isolated from normal rats and rats that had a bile duct ligation (BDL) 15, 30, and 60 days before the perfusion. Hepatic injury and transporter expression were measured in control and cirrhotic rats. Results: BDL induced a severe hepatic injury that increased over time with a down-regulation of the transporter expression. The extracellular space (assessed by Gd-DTPA perfusion) increased with the severity of the disease. Gd-BOPTA-induced SI enhancement remained similar in BDL-15 and BDL-30 rats than in control rats but significantly decreased in severe cirrhosis (BDL-60 rats). In comparison, the Mn-DPDP-induced SI enhancement decreases proportionally to the severity of the disease. Conclusion: During biliary cirrhosis, Gd-BOPTA-induced SI enhancement could not be related to the hepatic expression of transporters.

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Gd-BOPTA Transport Into Rat Hepatocytes: Pharmacokinetic Analysis of Dynamic Magnetic Resonance Images Using a Hollow-Fiber Bioreactor

Cited by 27 publications

References 47 publications

Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes

Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes

Direct evidence of the temperature dependence of Gd-BOPTA transport in the intact rat liver

Magnetic Resonance Imaging With Hepatospecific Contrast Agents in Cirrhotic Rat Livers

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