Protein Abundance of Hepatic Drug Transporters in Patients With Different Forms of Liver Damage

Abstract

Hepatocellular transporter levels were quantified using quantitative reverse transcription polymerase chain reaction and liquid chromatography-tandem mass spectrometry methods. Liver function deterioration (Child-Pugh class C) produced significant protein abundance (mean values) increase (to healthy livers) in P-gp (to 260% (CV (coefficient of variation) 82%)) and MRP4 (CV 230%) (not detected in healthy livers), decrease in MRP2 (to 30% (CV 126%)), NTCP (to 34% (CV 112%)), OCT1 (to 35% (CV 153%)), OATP1B1 (to 46% (CV 73%)), and OATP2B1 (to 27% (CV 230%)), whereas BSEP (CV 99%), MRP3 (CV 106%), OAT2 (CV 97%), OCT3 (CV 113%), and OATP1B3 (CV 144%) remained unchanged. Alcoholic liver disease produced significant protein downregulation of MRP2 (to 30% (CV 134%)), NTCP (to 76% (CV 78%)), OAT2 (to 26% (CV 117%)), OATP1B1 (to 61% (CV 76%)), OATP1B3 (to 79% (CV 160%)), and OATP2B1 (to 73% (CV 90%)) of healthy tissue values. Hepatitis C produced BSEP (to 47% (CV 99%)) and OATP2B1 (to 74% (CV 91%)) protein reduction. Primary biliary cholangitis and primary sclerosing cholangitis demonstrated P-gp and MRP4 protein upregulation (to 350% (CV 47%) and 287% (CV 38%), respectively). Autoimmune hepatitis revealed P-gp (to 410% (CV 49%)) and MRP4 (CV 96%) increase, and MRP2 (to 18% (CV 259%)) protein decrease. Drug transporters' protein abundance depends on liver pathology type and its functional state.Drug transporters have a major impact on the overall drug disposition, efficacy, toxicity, and drug-drug interactions. While transporters present at the basolateral membrane mediate the uptake of substrates from blood into hepatocytes and/or efflux of substrates in the opposite direction, transporters at the canalicular membrane mediate the excretion of substrates into bile. Transporters present in intracellular membranes sequester substrates in subcellular compartments within hepatocytes. The expression and function of transporters are subjected to complex regulatory mechanisms and may be affected by liver disease states and liver dysfunction.

Novel Technologies Enable Mechanistic Understanding and Modeling of Drug Exposure and Response

“…Again, significant disease‐related changes in the protein expression levels of key drug transporters are noted in liver samples from patients with NASH, providing crucial information relevant to understanding and predicting hepatic drug levels, targeting, and metabolism in patients with this common disease. The results are consistent with those of Drozdzik et al, 3 who not only find that expression levels of transporters are significantly different in livers from patients with NASH but that livers from patients with other diseases that affect liver function also show changes in transporter expression. These kinds of data can be incorporated into physiologically‐based pharmacokinetic (PBPK) models to predict disease‐induced changes in drug levels and exposure in patients with NASH and other diseases that affect liver function.…”

Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

“…MRP2 is the downregulated efflux transporter. On the contrary, the function of uptake carriers, namely, NTCP, OCT1, OATP1B1 and OATP2B1 decrease [13]. The decline in levels of the transporters implicated in bilirubin (the uptake transporters OATP1B1 and OATP1B3 and the efflux transporter MRP2) and bile salts handling correspond with the observed concentration changes of these endogenous transporter levels in liver failure [38].…”

“…In addition, multidrug and toxin extrusion protein 1 (MATE1; SLC47A1) is located in the apical hepatocyte membrane [3]. The most abundant transporters expressed in the liver are uptake carriers, namely, OATP1B3, OATP1B1, OCT1 and OATP2B1 (mediating the uptake of endogenous compounds like bilirubin and bile salts), whereas MATE1, P-gp, BCRP and MRP2 are the least present [12,13]. The enterocyte apical (luminal) membrane hosts uptake carriers, namely, OCT3, peptide transporter 1 (PEPT1, SLC15A1), apical sodium-dependent bile acid transporter (ASBT, SLC10A2) and monocarboxylic acid transporter 1 (MCT1, SLC16A1) as well as efflux function transporters, namely, P-gp, BCRP and MRP2.…”

Use of imaging to assess the activity of hepatic transporters

“…This can potentially be applied in drug development to assess the influence of hepatic transporters on the excretion of radiolabeled drugs, such as in transporter-mediated DDIs. Moreover, this approach bears considerable potential for diagnostic functional liver imaging as hepatic transporter activity changes in liver disease [13,14]. However, it is important to bear in mind that PET has some limitations, which can lead to a misinterpretation of the results.…”

“…Hepatic transporters are of great concern in drug development as they are important sources of pharmacokinetic variability, which may, in turn, lead to inter-individual variability in drug response as well as to drug adverse effects [3]. Important factors which can lead to variability in hepatic transporter activity include genetics, age, disease as well as the concomitant intake of other drugs [12][13][14][15][16]. The latter is referred to as transporter-mediated drug-drug interaction (DDI), in which the simultaneous intake of two drugs which interact with the same drug transporter(s) may change the activity of the transporter(s) as compared to a situation when each drug is taken alone [3,15].…”