1 research outputs found
Combined in Vitro–in Vivo Approach To Assess the Hepatobiliary Disposition of a Novel Oral Thrombin Inhibitor
Two
clinical trials and a large set of in vitro transporter experiments
were performed to investigate if the hepatobiliary disposition of
the direct thrombin inhibitor prodrug AZD0837 is the mechanism for
the drug–drug interaction with ketoconazole observed in a previous
clinical study. In Study 1, [<sup>3</sup>H]AZD0837 was administered
to healthy male volunteers (<i>n</i> = 8) to quantify and
identify the metabolites excreted in bile. Bile was sampled directly
from the jejunum by duodenal aspiration via an oro-enteric tube. In
Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics
of AZD0837, the intermediate metabolite (AR-H069927), and the active
form (AR-H067637) was investigated (<i>n</i> = 17). Co-administration
with ketoconazole elevated the plasma exposure to AZD0837 and the
active form approximately 2-fold compared to placebo, which may be
explained by inhibited CYP3A4 metabolism and reduced biliary clearance,
respectively. High concentrations of the active form was measured
in bile with a bile-to-plasma AUC ratio of approximately 75, indicating
involvement of transporter-mediated excretion of the compound. AZD0837
and its metabolites were further investigated as substrates of hepatic
uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell
monolayers and P-glycoprotein (P-gp) expressing membrane vesicles
identified AZD0837, the intermediate, and the active form as substrates
of P-gp. The active form was also identified as a substrate of the
multidrug and toxin extrusion 1 (MATE1) transporter and the organic
cation transporter 1 (OCT1), in HEK cells transfected with the respective
transporter. Ketoconazole was shown to inhibit all of these three
transporters; in particular, inhibition of P-gp and MATE1 occurred
in a clinically relevant concentration range. In conclusion, the hepatobiliary
transport pathways of AZD0837 and its metabolites were identified
in vitro and in vivo. Inhibition of the canalicular transporters P-gp
and MATE1 may lead to enhanced plasma exposure to the active form,
which could, at least in part, explain the clinical interaction with
ketoconazole