Transporter‐Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate

Abstract

The expression of hepatic transporters, including organic anion transporting polypeptides (OATPs) and multidrug resistance-associated proteins (MRPs), is altered in nonalcoholic steatohepatitis (NASH); however, functional data in humans are lacking. In this study, Tc-mebrofenin (MEB) was used to evaluate OATP1B1/1B3 and MRP2 function in NASH patients. Healthy subjects (n = 14) and NASH patients (n = 7) were administered MEB (∼2.5 mCi). A population pharmacokinetic model was developed to describe systemic and hepatic MEB disposition. Study subjects were genotyped for SLCO1B1 variants. NASH increased systemic and hepatic exposure (median ± 2 SE, healthy vs. NASH) to MEB (AUC : 1,780 ± 242 vs. 2,440 ± 775 μCi*min/L, P = 0.006; AUC : 277 ± 36.9 vs. 433 ± 40.3 kcounts*min/sec, P < 0.0001) due to decreased biliary clearance (0.035 ± 0.008 vs. 0.017 ± 0.002 L/min, P = 0.0005) and decreased V (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CL was reduced in NASH and also in healthy subjects with SLCO1B1 *15/*15 and *1A/*15 genotypes. The pharmacokinetics of drugs that are OATP1B1/1B3 and MRP2 substrates may be substantially altered in NASH.

Quantitative Proteomics and Mechanistic Modeling of Transporter‐Mediated Disposition in Nonalcoholic Fatty Liver Disease

“…Earlier clinical studies have shown that the systemic exposure to MEB, an OATP/MRP2/MRP3 probe substrate with extensive biliary elimination, is increased in biopsy‐verified NASH patients . Consistent with the NASH‐induced changes in transporter abundance, a PBPK model mechanistically accounting for the OATP/MRP2/MRP3‐mediated hepatobiliary disposition and verified with PK in healthy subjects (including a PK interaction with an OATP1B inhibitor, ritonavir), well recovered changes in MEB intravenous PK in NASH while implementing quantitative transporter expression differences and representative population demographics (i.e., obese population model).…”

“…For instance, elevated plasma levels of amidated bile acids (e.g., taurocholic acid and glycocholic acid) were noted in NASH subjects . Also the clearance of indocyanine green and MEB, both used as diagnostic agents to assess liver function, was shown to decrease in NASH subjects . Amidated bile acids and these two diagnostic agents are known substrates of OATP and NTCP.…”

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

“…Additional results were obtained with positron emission tomography probe substrates in the presence of RIF (Bauer et al, 2018b;Kaneko et al, 2018). MEB was also used as an imaging probe substrate by Ali et al (2018) to determine the OATP and MRP2 functions in patients with nonalcoholic fatty liver disease. The liver disease decreases both MEB CL in and CL int,bile with increased liver and systemic concentrations over time.…”

“…Liver imaging estimates concentrations that should be high enough for drugs targeting hepatocytes but low enough to avoid cell injury when the target is extrahepatic (Chu et al, 2013;Dollery, 2013;Guo et al, 2018). Pharmacokinetic models of liver images acquired over time estimate transfer rates and CLs between two compartments of the liver, as well as liver area under the curve (AUC) (Ali et al, 2018;Bauer et al, 2018a;Caillé et al, 2018;Kaneko et al, 2018;Leporq et al, 2018). Some of these studies suggest that liver concentrations might be more altered than systemic concentrations when inhibitors such as rifampicin (RIF) are concomitantly substrates of uptake transporters and decrease bile excretion rates (v bile ) Unadkat, 2016, 2018;Benet et al, 2018a;Kaneko et al, 2018).…”

Imaging techniques to study drug transporter function in vivo

“…Two studies found diminished liver enhancement with gadoxetate in carriers of SLCO1B1 SNPs without changes in plasma PK of gadoxetate, suggesting that genetic transporter variants may be signal confounders in gadoxetate-enhanced diagnostic liver MRI (Nassif et al, 2012;Okubo et al, 2013). One study examined liver distribution of [ 99m Tc]mebrofenin in healthy volunteers and patients with nonalcoholic steatohepatitis and found a diminished CL uptake,liver of [ 99m Tc]mebrofenin in healthy volunteers who were carriers of low/intermediate function SLCO1B1 genetic variants (Ali et al, 2017). It can be expected that transporter polymorphisms will also affect tissue uptake of other clinically used diagnostic radiotracers or contrast agents and should therefore be considered in the interpretation of imaging data.…”