What is the impact of metabolic dysfunction–associated steatotic liver disease on drug transport and metabolism?

KEYWORDS:

• MASLD
• MASH
• inflammation
• drug treatment
• drug metabolism
• drug transport
• adverse events

1. Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease all over the world. MASLD is already considered the second most common indication for liver transplantation in the U.S.A. after chronic hepatitis C infection [1]. A recent meta-analysis including 92 studies over 22 countries describes a global MASLD prevalence of 30% with regional differences. Global MASLD prevalence increased by +50% from 25% in 1990–2006 to 38% in 2016–2019. The highest prevalence is found in Latin America with 44% followed by the Middle East and North Africa, the lowest in Western Europe with 25% [2]. The prevalence is age-dependent with a strong association to all features of the Metabolic Syndrome (obesity, diabetes mellitus, hypertension, dyslipidemia). Therefore, the importance of MASLD in pharmacotherapy is rising. Given the fact that in the various stages of MASLD numerous metabolic enzymes and transporters are changed in their expression, the potential risk of pharmacokinetic disruptions was ascribed to more than 70 commonly used drugs recently [3]. Aim of this article is to summarize recent evidence from human studies and to draw conclusions for the care of this steadily rising subgroup of the general population.

2. Acquired changes in drug transport and metabolism in NASH livers

In most affected subjects, bland steatosis has a good prognosis with no or only mild disease progression [4]. In contrast, metabolic dysfunction–associated steatohepatitis (MASH) as the inflammatory disease entity shows a significant subset of patients with progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Recent data from placebo arms of clinical MASH trials show that 20–30% patients with MASLD will have NASH and 10–15% of these eventually progress to cirrhosis. Both inflammatory signaling activated in MASH livers and structural changes with loss of functional liver tissue in advanced fibrosis or cirrhosis confer acquired functional alterations that impact hepatic drug metabolism and transport (Figure 1).

Figure 1. Principles of phase 0-III metabolism regulation in steatotic liver disease (updated from Dietrich 2017). right panel: changes in hepatic transporter systems (phase 0 and III); left panel: changes in enzymes (phase I and II). Structural changes and inflammatory mediators are indicated as applicable.

Available evidence supports the view that several CYP isoforms, among them the most important 3A4, are reduced in expression and activity in NAFLD/MASLD [5–7]. Cytochrome P450 (CYP) 3A4 is responsible for phase-I-metabolism of more than 30% of commonly used drugs [8], implicating a broad clinical impact of these changes. The association of non-alcoholic fatty liver disease (NAFLD, this terminology is used for studies recruited under the former definition) and diabetes mellitus on CYP3A4 activity has recently been investigated in human liver tissue from brain-dead donors [7]. Microsomal in vitro CYP3A4 activity was 1.9- and 3.1-fold (p < 0.05) lower in bland steatosis and NASH than in normal donors and in line with a significantly lower CYP3A4 protein expression in bland steatosis and NASH donors. Diabetes was also associated with decreased CYP3A4 activity and protein expression. On the other hand, CYP2E1 seems to be upregulated, suggesting an important role in Acetaminophen toxicity, currently with little clinical evidence [9,10]. In a first case report of a NAFLD/MASLD patient, additional risk factors such as malnutrition and bariatric surgery were necessary to induce liver failure during high-dose acetaminophen use [11]. As a general principle, expression of many CYP enzymes changes with inflammatory and structural alterations during the progression from bland steatosis toward NASH/MASH and with the emergence of liver cirrhosis [12–14].

Data regarding human phase-II metabolism are less clear. The expression of specific uridine diphosphate-glucuronosyltransferase (UGT) and sulfotransferases (SULT) isoforms appears to be differentially regulated in human livers: Measurement of the glucuronidation and sulfonation of acetaminophen revealed no alterations in glucuronidation, whereas SULT activity was increased in steatosis compared with healthy controls but then decreased in the advanced NASH stage (compared with bland steatosis) [15]. Widespread redundancy in metabolism by several UGT isoforms precludes a specific lack of drug metabolism [5].

Transmembrane transport proteins from the solute carrier (SLC) superfamily generally mediate the secondary active uptake of endogenous and xenobiotic compounds into the hepatocyte, while transport proteins of the ABC family mediate their primary active, ATP-dependent, excretion into bile [16]. These hepatobiliary transport systems undergo specific regulation during inflammatory and cholestatic liver damage [14]. Organic anion transporter proteins (OATPs) most abundantly expressed in human liver are OATP1B1, OATP1B3, and OATP2B1 with partially overlapping substrate specificity including statins, angiotensin-II-receptor antagonists, and angiotensin-converting enzyme inhibitors as most frequently used drug classes [17]. In a recent systematic review across 10 cross-sectional studies, a significant reduction in expression and function of OATP1B3, OATP1B1, and OATP2B1 has been observed [18]. In contrast to an upregulation of basolateral efflux transporters including multidrug resistance proteins (MRP, officially now named ATP-binding cassette proteins class C (ABCC)) 3 and 4, MRP2 (ABCC2) as canalicular excretion transporter is functionally reduced in human fatty liver due to mislocalization or internalization [18]. Irrespective of the underlying chronic liver disease, deterioration of liver function to Child-Pugh stage C leads to a significant protein decrease (compared to healthy livers) in OATP1B1 (to 46%), OATP2B1 (to 27%), and MRP2 (to 30%) [19]. Changes in hepatobiliary excretion can enhance the toxicity of drugs dependent on these transporters. As examples with broad clinical relevance, this comprises methotrexate and statins as well as ezetimibe. Downregulation of basolateral uptake and biliary efflux transporters impedes drug metabolism, while upregulation of basolateral efflux transporters such as MRP4 (ABCC4) provides the ability of sinusoidal re-secretion, resulting in higher systemic retention. However, while the effects of these transporter changes in pharmacokinetic studies are significant, clinical effects still remain rare or are not described sufficiently yet (reviewed in [5]). In line with this impression, there is a belief in the drug-induced liver injury (DILI) field (without clear clinical data) that MASLD patients are not more prone to DILI but are at higher risk for complications and adverse outcomes from DILI [20].

Additionally, it must be emphasized that MASLD-related alterations in metabolism and transport may be more pronounced in carriers of genetic variants predisposing to adverse effects of common medical drugs or with other accumulating risk factors. Until now, mostly non-serious adverse events have been described in MASH patients, so that most drug treatments seem to be safe, when titrated carefully to the recommended doses or controlled by determination of trough concentrations (reviewed in [5]).

3. Difficulties in measuring the clinical impact on drug metabolism in patients with MASH: why we do not know exactly what MASLD does to drug metabolism

There are two major problems in the grading of the impact of MASLD on drug transport and metabolism. The first problem is more methodological (‘basic science-clinical conflict’): There is a clear gap between basic science methods and measured clinical impact due to the complexity of metabolism pathways. Firstly, many studies only use in vitro methods such as microsomal or cell models in estimating the influence of isolated metabolic enzymes on metabolism of a given drug. Secondly, changes in metabolic enzymes often are only measured on the level of transcription (mRNA) or translation (protein expression), ignoring frequent posttranscriptional modifications or inactivity of transporters by mislocalization in cell compartments (e.g. with the important transporter MRP2, see above). Even specific changes in enzyme activity do not necessarily reflect clinical importance in drug metabolism since there is widespread redundancy and little specificity in the allocation of drugs to metabolic enzymes. Several years ago it has been shown that dipeptidyl peptidase-4 activity is increased in NAFLD patients but not in diabetic patients [21], indicating that metabolic changes in NAFLD/MASLD are not confined to classic metabolic pathways. It would be straightforward to hypothesize that this increase in activity may result in reduced treatment effects of GLP-1 analogs which was not detected in recent clinical trials [22]. Again, this example shows the gap between molecular measurements and clinical relevance. To date, the field still lacks reliable tools for measuring whole body metabolism.

The second aspect is more epidemiological: Due to the proximity of MASLD to the metabolic syndrome and to metabolic liver damage, it is difficult to estimate the MASLD-specific contribution to metabolic changes. By definition, most MASLD patients are obese and/or suffer from type 2 diabetes (T2DM). Systemic effects of obesity and T2DM alone contribute to significant changes in metabolism, including carcinogens and drugs with clinical effects on development and treatment of diseases [23,24], although the results of existing studies are conflicting. The specific contribution of MASLD is unclear (‘epidemiological conflict’). In general, chronic inflammation in T2DM patients via upregulation of TNFα and IL-6 (an important molecular hallmark of MASLD) may modify expression and activity of metabolism enzymes and transporters [25]. As another mechanism, when structural hepatic damage progresses, molecular changes of liver cirrhosis develop as has been shown for various hepatic diseases irrespective of the disease entity [26]. Such cirrhosis-related changes are not specific to fatty liver. It is therefore impossible at this stage of scientific evidence, to estimate the particular contribution of hepatic steatosis or MASH on drug metabolism.

Both problems can be solved only by a new study culture for this important and highly prevalent disease. Firstly, we need studies dedicated to the clinical effects of obesity and MASLD on drug metabolism with endpoints such as drug blood concentration and excretion, side effects, toxicity and, if possible, at least surrogate markers of target engagement and/or treatment success. Secondly, and easier to realize, existing studies (prospectively or retrospectively by sub-group analysis) need to be analyzed systematically regarding side effects and treatment effects in patients with obesity and MASLD, also according to fibrosis stage. A first step is guidelines regarding DILI in MASLD patients as published in 2019 [20], but these guidelines (initiated for studies in NAFLD/MASLD patients) should be extended to selected general studies with importance for MASLD patients (e.g. diabetes, obesity, cardiovascular diseases, pain and cancer treatment).

4. Expert opinion

Given the frequency of MASLD today, a high degree of drug treatment appears safe and well tolerated in these patients despite considerable changes in hepatic uptake, distribution, metabolism, and transport of drugs. However, in many basic science studies, NASH/MASH has widespread systemic consequences on metabolism, causing changes in biliary excretion, blood concentrations, and renal handling of drugs, leading to alterations in drug efficacy or toxicity under specific circumstances. These consequences are not confirmed in clinical studies due to the complexity of the metabolic network and lack of clinical data. Future clinical drug studies should focus on this special patient population in order to specify changes in bioavailability, to identify specific risk factors and to avoid serious adverse events in MASLD patients.

Declaration of interest

CG Dietrich has nothing to declare. A Geier served as a steering committee member or advisor for AbbVie, Alexion, Bayer, BMS, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis and as speaker for AbbVie, Advanz, Alexion, BMS, Burgerstein, CSL Behring, Falk, Gilead, Intercept, Merz, MSD, Novartis, NovoNordisc, Roche. He received research support from Intercept and Falk (both NAFLD CSG), Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.