ABSTRACT
A semiphysiologically based pharmacokinetic (semi-PBPK) model was developed to describe a unique blood, liver, and bile clinical data set for the hepatobiliary imaging agent (99m)Technetium-mebrofenin ((99m)Tc-mebrofenin), and to simulate sites/mechanisms of a (99m)Tc-mebrofenin-ritonavir drug-drug interaction (DDI). The transport inhibitor ritonavir (multiple-dose: 2 × 300 mg) significantly increased systemic (99m)Tc-mebrofenin exposure as compared with control (4,464 ± 1,861 vs. 1,970 ± 311 nCi min/ml; mean ± SD), without affecting overall hepatic exposure or biliary recovery. A novel extrahepatic distribution compartment was required to characterize (99m)Tc-mebrofenin disposition. Ritonavir inhibited (99m)Tc-mebrofenin accumulation in human sandwich-cultured hepatocytes (SCH) (half maximal inhibitory concentration (IC50) = 3.46 ± 1.53 µmol/l). Despite ritonavir accumulation in hepatocytes, intracellular binding was extensive (97. 6%), which limited interactions with multidrug resistance protein 2 (MRP2)-mediated biliary excretion. These in vitro data supported conclusions from modeling/simulation that ritonavir inhibited (99m)Tc-mebrofenin hepatic uptake, but not biliary excretion, at clinically relevant concentrations. This integrated approach, utilizing modeling, clinical, and in vitro data, emphasizes the importance of hepatic and extrahepatic distribution, assessment of inhibitory potential in relevant in vitro systems, and intracellular unbound concentrations to assess transporter-mediated hepatic DDIs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e20; doi:10.1038/psp.2012.21; advance online publication 2 January 2013.
ABSTRACT
The biliary clearance (Cl(biliary)) of three compounds was estimated using sandwich-cultured human hepatocytes (SCHH) and compared with Cl(biliary) values measured in vivo. Tc-99m sestamibi (MIBI) Cl(biliary) was determined in seven healthy volunteers using an oroenteric catheter to aspirate duodenal secretions, and gamma scintigraphy to determine gallbladder contraction; this technique was used previously to determine Tc-99m mebrofenin (MEB) and piperacillin (PIP) in vivo Cl(biliary). In vitro Cl(biliary) of MEB, MIBI, and PIP was quantified in SCHH as the ratio of mass excreted into bile canaliculi and area under the blood concentration-time curve (AUC) in medium. MIBI Cl(biliary) in vivo was 5.5+/-1.2 mL/min/kg (mean+/-SD). The rank order of Cl(biliary) predicted from SCHH corresponded well with the in vivo Cl(biliary) values in mL/min/kg for MEB (7.44 vs 16.1), MIBI (1.20 vs 5.51), and PIP (0.028 vs 0.032). In conclusion, the methods developed allowed for reproducible quantification of Cl(biliary) of drugs in healthy humans and prediction of Cl(biliary) from in vitro data.
