Influence of the OATP1B1 and OATP1B3 Genotype on the Hepatic Uptake of Primovist®
Condition: Pharmacokinetics; MRI; Liver; Drug Transporter; Gd-EOB-DTPA
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The objective of the study is to assess the hepatic uptake of Primovist® after intravenous
      administration of 25 µmol/kg body weight in 56 healthy volunteers and in 60 patients with a
      liver disease in dependence on the OATP1B1- and OATP1B3-genotype.
    

Detailed description: 
      Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gadoxetate, Gd-EOB-DTPA,
      Primovist®) is a newly developed paramagnetic hepatobiliary contrast agent for magnetic
      resonance imaging (MRI) based on the extracellular fluid marker gadopentetate (Magnevist®).
      After intravenous administration, Gd-EOB-DTPA distributes rapidly within the intravascular
      and extracellular spaces and is taken up selectively by hepatocytes. The compound is
      eliminated from the blood and from the body mainly by two pathways: glomerular filtration of
      the kidneys and hepatobiliary excretion. There is many evidence that the hepatic uptake of
      Gd-EOB-DTPA from the sinusoidal blood is influenced by specific hepatic transporters of the
      organic anion transporter (OATP) family.

      For the highly liver specific agent has been demonstrated that it markedly improves the
      quality of detection of focal liver lesions (adenoma, focal nodular hyperplasia,
      hepatocellular carcinoma). Because gadoxetate is taken up both in the normal liver parenchyma
      as well as in focal liver lesions of hepatocellular origin, it allows to distinguish between
      hepatocyte-containing and non-hepatocyte-containing tissue. In some indications (e.g.
      preoperative evaluation of patients with hepatocellular carcinoma), liver-specific contrast
      media like Gd-EOB-DTPA are superior to biphasic spiral computertomography.

      Hepatic enhancement after intravenous administration of Gd-EOB-DTPA is known to be inhibited
      by bromosulfophthalein, taurocholate and rifampicin. Obviously, Gd-EOB-DTPA and other drugs
      compete for the organic anion transporters of the hepatocytes. In Oatp1 cRNA injected oocytes
      of Xenopus leavis, a saturable uptake of gadoxetic acid has been demonstrated. Since the
      human organic anion transporting polypeptide (OATP) 1B1 (previous names: OATP-C, L-ST1,
      OATP2), which is responsible for the hepatic uptake of several endogenous and exogenous
      compounds like bile acids, bilirubin, peptides, steroid conjugates, thyroid hormones,
      methotrexate, statins and ezetimibe, is predominantly expressed in the basolateral membrane
      of hepatocytes, Gd-EOB-DTPA might be a substrate of this uptake transporter.

      Because there were described functional relevant single nucleotide polymorphisms (SNP) for
      OATP1B1, which were responsible for markedly reduced transporter function and which were even
      shown to alter plasma concentrations of pravastatin and ezetimibe in vivo, we want to
      investigate the impact of several genotypes of OATP1B1 on disposition of Gd-EOB-DTPA. While
      *15 and *5 carriers of OATP1B1 were described to exhibit decreased lipid-lowering potency and
      increased statin-induced myopathy, *1b carriers exerted a significantly reduced
      bioavailability of ezetimibe. Due to the fact that the interesting haplotypes like OATP1B1
      *15 and *1b are in fact relatively common in European subjects, we intend to define its
      influence on Gd-EOB-DTPA pharmacokinetics and on different signal intensities in magnetic
      resonance imaging of the liver.

      OATP 1B3 (previous names: OATP8,LST-2), which is also predominantly expressed in the
      basolateral membrane of hepatocytes, is responsible for the hepatic uptake of several
      endogenous and exogenous compounds like bile acids, 17β-glucuronosyl estradiol, BSP or
      digoxin.

      There is evidence from very recent experimental studies in our laboratory, that Primovist® is
      not only a substrate of OATP1B1 but also of the second liver specific uptake transporter
      OATP1B3. The MRT contrast agent inhibits the uptake of BSP in HEK tansfected with human
      OATP1B1 and OATP1B3 and it is also better taken up by these cells than by non-transfected
      parental cells. Therefore, we concluded that OATP1B3 might be additionally to OATP1B1 an
      specific uptake transporter in human liver.

      Very recently, at least six single nucleotide polymorphisms (SNP) of OATP1B3 have been
      described in literature. At least two of them were described to be of functional relevance:
      334T>G (Ser112Ala) and 699G>A (met233Ile). The allele frequencies of the 334T>G and 699G>A
      variants in European Caucasians were reported to be 74 % and 71%, respectively.

      The influence of these amino-acid substitutions on OATP1B3 transport function and cellular
      localization seems to be substrate and cell line dependent. In man, it was shown that
      OATP1B3*2 influences obviously the hepatic uptake of erythromycin and hence the results of
      the ERMBT (erythromycin breath test) in cancer patients.

      Therefore, carriers of OATP1B3 334T>G and OATP1B3 699G>A are planned to be included into the
      study with Primovist® to confirm whether the selective hepatic uptake carrier OATP1B3 is
      involved in hepatic uptake of the MRI contrast agent additionally to OATP1B1.

      In several animal studies a reduced enhancement of Gd-EOB-DTPA was observed in acute
      hepatitis, fatty liver and cholestasis models. Obviously the hepatic uptake of gadexotate
      might be determined by liver diseases which lead to an altered function of hepatocytes.
      Therefore it is a further aim of the study to assess the influence of liver diseases on
      Gd-EOB-DTPA pharmacokinetics and signal intensity and its possible modification by the
      OATP1B1-genotype in 60 patients which are subjected to MR imaging of the liver.
    

Intervention name(s): Primovist® 0,25 mmol/ml solution for injection; MRI
Intervention type(s): Drug; Device
Intervention description(s): intravenous bolus injection of 25 µmol/kg (=0,1 ml/kg) body weight Primovist® and blood sampling before (serum blank) and 6, 11, 21, 31, 45, 65, 95, 125 min and 3, 4, 6, 8, 12, 24 and 48 h after drug administration; lmaging of 20 slices (thickness: 3 mm; max. time of imaging 10 s) before and 0.25, 1, 2, 3, 4, 5, 7, 8, 9, 10, 20, 30, 40, 50, 60, 90 and 120 min after intravenous bolus injection of 25 µmol/kg (=0,1 ml/kg) body weight Primovist®
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: pharmacokinetics; MRI; liver; drug transporter; Gd-EOB-DTPA