Dual Plasma Sampling Method To Determine The Hepatic And Renal Clearance Of The 2 Diastereoisomers Of Gd-EOB-DTPA

Gadoxetate disodium（Gd-EOB-DTPA）is a novel type of Magnetic Resonance Imaging（MRI）contrast agent,which can be specifically uptake by hepatocytes.Gd-EOB-DTPA has rapidly increased in clinical practice for detection and identification of hepatic occupied lesions,and for the evaluation of liver reserve function in particular.Gd-EOB-DTPA is a chemical derivative of Gd-DTPA,with a lipophilic moiety（an ethoxybenzyl group,EOB）added to the DTPA backbone,thus the molecular structure has both hydrophilic and lipophilic properties,resulting in 2 elimination routes through the liver and kidney simultaneously.Gd-EOB-DTPA consists of 2 diastereoisomers（Gd-A and Gd-B;65:35wt/wt）,which can be determined separately by high-performance liquid chromatography（HPLC）.The 2 diastereoisomers demonstrated different ratio in rats’bile from that in the drug administered implying different hepatic elimination rate.As stated previously,individual measurement of the hepatic and renal clearance of the 2 diastereoisomers will extend our knowledge of pharmacokinetics of Gd-EOB-DTPA and may be helpful to estimate hepatic and renal function in clinical practice.This research mainly aimed at developing a method to determine hepatic and renal clearance of the 2 diastereoisomers（Gd-A,Gd-B）of Gd-EOB-DTPA separately,analyze the potential relationship between the hepatic store function and the liver clearance rate of the 2 diastereoisomers.Then the experimental procedure was to prospectively enroll 41 patients with liver disease.For each patient,1 m L of iopromide（to determine glomerular filtration rate[GFR]）was coadministered with Gd-EOB-DTPA（Gd-A and Gd-B;65:35 wt/wt）.The plasma clearances of Gd-A（PCL-Gd A）and Gd-B（PCL-Gd B）as well as the iopromide（GFR）were generated by using dual plasma sampling method.Meanwhile,the patient’s urine was collected for measurement of renal clearance of Gd-A（RCL-Gd A）and Gd-B（RCL-Gd B）to confirm its agreement with GFR.Hepatic clearances of Gd-A（HCLGd A）and Gd-B（HCL-Gd B）were calculated by subtracting the GFR from PCLGd A and PCL-Gd B,respectively,and were correlated with indocyanine green（ICG）15 minutes retention rate（ICG R15）.Pharmacokinetic parameters were compared between the two isomers and between Child–Pugh classifications using student’s t test.The final result show that both RCL-Gd A and RCLGd B demonstrated a good correlation and agreement to GFR（statistics shown in the main body）.HCL-Gd A demonstrated a strong negative correlation（r=-0.86,P<0.001）with ICG R15 and was much higher than HCL-Gd B(116.18±75.48 vs 19.74±14.24ml·min^-1,P<0.001).HCL-Gd B demonstrated aweak correlation（r=-0.26,P=0.102）with ICG R15.HCL-Gd A of noncirrhosis and Child-Pugh class A(151.74±68.28 ml·min^-1,n=26)was higher than that of Child-Pugh class B(54.54±39.13 ml·min^-1,n=15;P=0.001).We concluded that a practical method was established for the determination of hepatic and renal clearance of the 2 isomers of Gd-EOB-DTPA.The 2 isomers have equal renal clearance and different hepatic clearance.The HCL-Gd A may serve as a novel marker to reflect liver function reserve.