Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast–enhanced Magnetic Resonance Imaging

Abstract

To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established.

A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function

“…Neither the established biomarkers of liver injury, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, nor the novel biomarker miRNA-122, showed a difference between rifampicin and vehicle treated groups two hours after dosing with rifampicin. This confirms the results of Lenhard et al where changes in transporter function were observed without an increase in liver injury enzymes [ 19 ]. In contrast, both total and direct bilirubin were elevated.…”

In Vivo Imaging in Pharmaceutical Development and Its Impact on the 3Rs

“…Finally, as MRI, US, and CT imaging can be used to monitor treatment effects during studies, recovery of these effects can also be monitored to determine the permanence of treatment or return animals to colonies, for example, thereby promoting the 3Rs. For example, Lenhard et al (2016) applied dynamic contrast-enhanced MRI to detect changes in hepatobiliary transporter function as a result of amiodarone-induced hepatic phospholipidosis before, during, and 2 weeks after cessation of amiodarone treatment. The calculated rates of contrast agent wash-out, which is dependent on efflux transporter function, decreased with treatment and fully recovered after cessation of treatment.…”