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. 2017 Dec 22:10.1002/cpt.997.
doi: 10.1002/cpt.997. Online ahead of print.

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

Izna Ali  1 , Jason R Slizgi  1 , Josh D Kaullen  1 , Marija Ivanovic  2 , Mikko Niemi  3   4 , Paul W Stewart  5 , Alfred S Barritt 4th  6 , Kim L R Brouwer  1
Affiliations

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

Izna Ali et al. Clin Pharmacol Ther. .

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, 99m 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 (AUC0-300,blood : 1,780 ± 242 vs. 2,440 ± 775 μCi*min/L, P = 0.006; AUC0-180,liver : 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 Vcentral (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CLuptake 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.

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Conflict of interest statement

Conflict of Interest: The authors declared no competing interests for this work.

Figures

Fig. 1
Fig. 1. 99mTc-mebrofenin blood concentration vs. time curves and liver scintigraphy vs. time curves in healthy subjects (blue) and patients with NASH (red)
Data represent mean±SD.
Fig. 2
Fig. 2. Schematic of the pharmacokinetic model describing 99mTc-mebrofenin disposition
The final structural model that best described the data included a central, peripheral and a liver compartment. 99mTc-mebrofenin was excreted into bile from the liver compartment.
Fig. 3
Fig. 3. Concentration-time profiles of observed data and model predictions
Observed data are depicted by circles and the model predictions for each individual subject are depicted by the curves.
Fig. 4
Fig. 4. Hepatic uptake clearance (CLuptake) and SLCO1B1 genotype in healthy subjects and NASH patients
The subgroups with intermediate function (IF) and low function (LF) genotypes were combined (due to the limited sample sizes) for comparison to the NASH and healthy subgroups with normal function (NF) genotypes. The null hypothesis “no distributional differences among the three populations” was tested using a Kruskal-Wallis procedure of size α=0.05 conditionally followed by paired comparisons using Dunn’s procedure. Legend: * p < 0.05, n.s. p ≥ 0.05.
See this image and copyright information in PMC

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