Interindividual Diversity in Expression of Organic Anion Uptake Transporters in Normal and Cirrhotic Human Liver

Taniguchi, Tatsuya; Zanetti-Yabur, Alana; Wang, Pijun; Usyk, Mykhaylo; Burk, Robert D.; Wolkoff, Allan W.

doi:10.1002/hep4.1489

Cited by 19 publications

(17 citation statements)

References 48 publications

(56 reference statements)

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“…This study and other recent reports suggest variability in the impact of cirrhosis on the expression of transporters according to the disease severity and the underlying pathophysiology (viral, alcoholic, and biliary diseases). ,, Drozdzik et al showed a progressive decline in the expression of NTCP, OATP1B1/2B1, OCT1, and MRP2 in line with our findings, but we also showed a progressive decline in the expression of BSEP, MRP3, OAT2, OCT3, and OATP1B3 in cirrhosis, which they did not. It is worth noting that associated diseases to cirrhosis in the two sets of samples are different (ours includes NAFLD, cancer, and cholestasis, while Drozdzik et al.…”

Section: Discussionsupporting

confidence: 92%

Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

et al. 2021

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Liver cirrhosis is a chronic disease that affects the liver structure, protein expression, and overall metabolic function. Abundance data for drug-metabolizing enzymes and transporters (DMET) across all stages of disease severity are scarce. Levels of these proteins are crucial for the accurate prediction of drug clearance in hepatically impaired patients using physiologically based pharmacokinetic (PBPK) models, which can be used to guide the selection of more precise dosing. This study aimed to experimentally quantify these proteins in human liver samples and assess how they can impact the predictive performance of the PBPK models. We determined the absolute abundance of 51 DMET proteins in human liver microsomes across the three degrees of cirrhosis severity ( n = 32; 6 mild, 13 moderate, and 13 severe), compared to histologically normal controls ( n = 14), using QconCAT-based targeted proteomics. The results revealed a significant but non-uniform reduction in the abundance of enzymes and transporters, from control, by 30–50% in mild, 40–70% in moderate, and 50–90% in severe cirrhosis groups. Cancer and/or non-alcoholic fatty liver disease-related cirrhosis showed larger deterioration in levels of CYP3A4, 2C8, 2E1, 1A6, UGT2B4/7, CES1, FMO3/5, EPHX1, MGST1/3, BSEP, and OATP2B1 than the cholestasis set. Drug-specific pathways together with non-uniform changes of abundance across the enzymes and transporters under various degrees of cirrhosis necessitate the use of PBPK models. As case examples, such models for repaglinide, dabigatran, and zidovudine were successful in recovering disease-related alterations in drug exposure. In conclusion, the current study provides the biological rationale behind the absence of a single dose adjustment formula for all drugs in cirrhosis and demonstrates the utility of proteomics-informed PBPK modeling for drug-specific dose adjustment in liver cirrhosis.

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Section: Discussionsupporting

confidence: 92%

Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

et al. 2021

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“…These transporters form a superfamily of membrane-solute carriers characterized by significant functional diversity and a widespread role in the transport of endo/xenobiotics ( Hagenbuch and Meier, 2004 ). There is scarce data on whether they are involved in the brain transport of psychotropics, but we know that transport of DHEA-S and opioids occurs via OATP1A2 and a small sex difference favoring women was recently reported ( Asaba et al, 2000 ; Gao et al, 2000 ; Taniguchi et al, 2020 ). However, DHEA administration led to a gender-neutral Oatp1a1 and Oatp1b2 decrease and a further decrease in Oatp1a4 expression only in males ( Rost et al, 2005 ).…”

Section: Organic Anion Transporting Polypeptidesmentioning

confidence: 99%

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Dalla

Pavlidi

Sakelliadou

et al. 2022

Front. Behav. Neurosci.

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Treatment of neuropsychiatric disorders relies on the effective delivery of therapeutic molecules to the target organ, the brain. The blood–brain barrier (BBB) hinders such delivery and proteins acting as transporters actively regulate the influx and importantly the efflux of both endo- and xeno-biotics (including medicines). Neuropsychiatric disorders are also characterized by important sex differences, and accumulating evidence supports sex differences in the pharmacokinetics and pharmacodynamics of many drugs that act on the brain. In this minireview we gather preclinical and clinical findings on how sex and sex hormones can influence the activity of those BBB transporter systems and affect the brain pharmacokinetics of psychotropic medicines. It emerges that it is not well understood which psychotropics are substrates for each of the many and not well-studied brain transporters. Indeed, most evidence originates from studies performed in peripheral tissues, such as the liver and the kidneys. None withstanding, accumulated evidence supports the existence of several sex differences in expression and activity of transport proteins, and a further modulating role of gonadal hormones. It is proposed that a closer study of sex differences in the active influx and efflux of psychotropics from the brain may provide a better understanding of sex-dependent brain pharmacokinetics and pharmacodynamics of psychotropic medicines.

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“…There are already pieces of evidence that female rats have greater BBB permeability of taurocholate and atorvastatin, which are carried by Oatp1a4/Slco1a4 (an ortholog for human OATP1A2), compared to the corresponding brain uptake of these compounds with male rats (151). A similar kind of trend has been seen in RNA expression of OATP1A2 collected from the human liver samples; females had approximately twice greater OATP1A2 mRNA expression compared to that in men (P < 0.05) (152). Therefore, more studies are warranted to elucidate the age-, race-, and gender-related effects on the pharmacoproteomics, not only OATP1A2 substrates but also other transporters at the CNS-barriers (Fig.…”

Section: Prospectsmentioning

confidence: 60%

Pharmacoproteomics of Brain Barrier Transporters and Substrate Design for the Brain Targeted Drug Delivery

et al. 2022

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One of the major reasons why central nervous system (CNS)-drug development has been challenging in the past, is the barriers that prevent substances entering from the blood circulation into the brain. These barriers include the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), blood-cerebrospinal fluid barrier (BCSFB), and blood-arachnoid barrier (BAB), and they differ from each other in their transporter protein expression and function as well as among the species. The quantitative expression profiles of the transporters in the CNS-barriers have been recently revealed, and in this review, it is described how they affect the pharmacokinetics of compounds and how these expression differences can be taken into account in the prediction of brain drug disposition in humans, an approach called pharmacoproteomics. In recent years, also structural biology and computational resources have progressed remarkably, enabling a detailed understanding of the dynamic processes of transporters. Molecular dynamics simulations (MDS) are currently used commonly to reveal the conformational changes of the transporters and to find the interactions between the substrates and the protein during the binding, translocation in the transporter cavity, and release of the substrate on the other side of the membrane. The computational advancements have also aided in the rational design of transporter-utilizing compounds, including prodrugs that can be actively transported without losing potency towards the pharmacological target. In this review, the state-of-art of these approaches will be also discussed to give insights into the transporter-mediated drug delivery to the CNS.

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Interindividual Diversity in Expression of Organic Anion Uptake Transporters in Normal and Cirrhotic Human Liver

Cited by 19 publications

References 48 publications

Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Pharmacoproteomics of Brain Barrier Transporters and Substrate Design for the Brain Targeted Drug Delivery

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