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Transporter‐Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate
Author(s) -
Ali Izna,
Slizgi Jason R.,
Kaullen Josh D.,
Ivanovic Marija,
Niemi Mikko,
Stewart Paul W.,
Barritt Alfred S.,
Brouwer Kim L.R.
Publication year - 2018
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.997
Subject(s) - multidrug resistance associated protein 2 , slco1b1 , transporter , organic anion transporter 1 , pharmacokinetics , medicine , population , pharmacology , endocrinology , chemistry , biology , genotype , atp binding cassette transporter , biochemistry , gene , single nucleotide polymorphism , environmental health
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 (AUC 0‐300,blood : 1,780 ± 242 vs. 2,440 ± 775 μCi*min/L, P = 0.006; AUC 0‐180,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 V central (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CL uptake 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.