https://orcid.org/0000-0001-7652-5194
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The whole concept of NAFLD has now moved into metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize the strong metabolic derangement as the basis of the disease. Several studies have suggested that hepatic gene expression was altered in NAFLD and NAFLD-related metabolic comorbidities, particularly mRNA and protein expression of phase I and II drug metabolism enzymes (DMEs). NAFLD may affect the pharmacokinetic parameters. However, there were a limited number of pharmacokinetic studies on NAFLD at present. Determining the pharmacokinetic variation in patients with NAFLD remains challenging. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated. More objective and rigorous studies are required to confirm these pharmacokinetic changes. We have also summarized the substrates of the DMEs aforementioned. In conclusion, DMEs play an important role in the metabolism of drugs. We hope that future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD.
1. Introduction
The biotransformation processes of drugs in vivo are mainly divided into two phases, phase I and phase II drug metabolic reactions. Phase I metabolism consists of functionalization reactions, mainly involving cytochrome P450 (CYP450) enzymes. Phase II drug metabolism is a conjugation reaction that includes glucuronidation, sulfation, and glutathione coupling. The most common phase II drug metabolism enzymes (DMEs) are uridine 5′-diphospho-glucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), and sulfotransferases (SULTs) (Almazroo et al. Citation2017). DMEs are mainly found in the liver, lung, kidney, small intestine, placenta, and skin, but the highest levels are located in the intestinal epithelial cells and the liver (Danielson Citation2002). In chronic liver disease states, the expression and activity of phase I and II DMEs could be altered. The alterations potentially affect the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination (Verbeeck Citation2008).
Nonalcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is defined imageologically or histologically as the presence of hepatic steatosis in absence of secondary hepatic fat accumulation (such as significant alcohol consumption, use of steatogenic medication or hereditary disorders et al.). NAFLD is caused by lipid and peripheral free fatty acids accumulation in the liver. NAFLD is also an umbrella term that encompasses a range from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH is a more progressive form of NAFLD. A small group of patients can develop NASH, ranging from 3 to 5% (Chalasani et al. Citation2012). NASH is defined as a more severe state of vacuolation, inflammation, and hepatocyte damage (Friedman et al. Citation2018). Generally, NASH is accompanied by pericellular fibrosis and may progress to fibrosis, cirrhosis, or hepatocellular carcinoma (Oseini and Sanyal Citation2017). In 2016, the global NAFLD prevalence was 25%; this increased to >30% in 2019. Prevalence in Asia, Latin America, and Middle East-North Africa was 30.8%, 34.5%, and 42.6%, respectively (Henry et al. Citation2022). In addition, a large proportion of patients with NAFLD have metabolic comorbidities. Metabolic comorbidities encompass obesity (51.34%), type 2 diabetes mellitus (T2DM) (22.51%), hypertension (39.34%), dyslipidemia (69.16%), and metabolic syndrome (42.54%), with insulin resistance as the common underlying pathophysiology (Cobbina and Akhlaghi Citation2017; Sakurai et al. Citation2021). While NAFLD largely increases the risk of cardiovascular disease and extrahepatic cancers. As a result, the burden of NAFLD has become a major public health issue (Zhou, Zhou, et al. Citation2020).
Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of NAFLD, which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) (Lin et al. Citation2020; Gofton et al. Citation2022). The whole concept of NAFLD has now moved into MAFLD to emphasize the strong metabolic derangement as the basis of the disease. MAFLD is diagnosed based on evidence of hepatic steatosis (detected by imaging, blood biomarkers, or liver histology) and the presence of any one of the following three criteria, namely overweight/obesity, presence of T2DM, or evidence of metabolic dysregulation (Eslam et al. Citation2020). Metabolic dysfunction in this context encompasses obesity, T2DM, hypertension, dyslipidemia, and metabolic syndrome (a collection of clinical conditions including hypertension, atherosclerotic dyslipidemia, obesity, insulin resistance, or T2DM). Whether the variation of DMEs in NAFLD was consisted with those in NAFLD-related metabolic comorbidities remains poorly understood.
Due to the uncertain inner mechanisms of NAFLD, no valid therapy has been approved. Current first-line treatments rely on dietary management, lifestyle modification, and physical exercise. There are many drugs targeting diverse molecular mechanisms of NAFLD in the pipeline, such as dapagliflozin, aramchol, resmetirom, semaglutide, and lanifibranor (Negi et al. Citation2022). Existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have also been considered in the management of NAFLD and NAFLD-related metabolic comorbidities (Polyzos et al. Citation2020; Negi et al. Citation2022). Several studies found that the expression and activity of DMEs were altered in NAFLD and NAFLD-related metabolic comorbidities (Buechler and Weiss Citation2011; Cobbina and Akhlaghi Citation2017; Wang et al. Citation2020). These alterations could be potential sources of drug variability in patients with NAFLD and could have serious consequences on safety and efficacy, yet it remains unclear. In this review, we summarized the current common animal models of NAFLD and the variation of phase I and II DMEs in NAFLD and NAFLD-related metabolic comorbidities. Meanwhile, we have a specific focus on the pharmacokinetics changes and their impact on clinical outcomes for patients with NAFLD.
2. Animal models of NAFLD
At present, liver biopsy is the gold standard for characterizing liver histology in patients with NAFLD. However, it is expensive and several studies have indicated significant risks and complications associated with liver biopsies, including pain, major bleeding, and death (Chalasani et al. Citation2012). Because collecting liver tissues from NAFLD patients was difficult due to the invasive nature of the technique, animal models (mice or rats) were generally used to analyze gene alterations in NAFLD. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models (). And most models successfully mimicked the histological pattern of NAFLD.
Table 1. The most commonly used mouse and rat models of NAFLD.
2.1. Dietary induction
Dietary induction models of NAFLD were established by feeding mice or rats in high-fat, sugar, cholesterol, methionine, and choline-deficient diets. There were three types of diet-induced models depending on the feeding component. The first type was defined by reduced lipid export or catabolism ((methionine and choline-deficient diet (MCDD); choline-deficient l-amino acid-defined diet (CDAAD)) (Nakanishi et al. Citation2019; Zhang, Li, et al. Citation2021). The second type included models with increased lipid import or synthesis in the liver (fructose, high-fat emulsion, high-fat diet (HFD)) (Zou et al. Citation2006; Gao et al. Citation2020; Cho et al. Citation2021). The third type was an HFD combined with another diet, including a high-fat high-fructose diet (HFHFD), choline-deficient high-fat diet (CDHFD), high-fat high-sucrose diet (HFHSD), and high-fat high-cholesterol diet (HFHCD) (Yan et al. Citation2018; Baiges-Gaya et al. Citation2021; Hong et al. Citation2022; Lad et al. Citation2022). Hepatic steatosis, hepatic lipid droplet formation, hepatocyte ballooning, inflammatory cell infiltration, liver damage, and liver fibrosis were frequently observed in these models. Dietary induction models of NAFLD have been listed in .
2.2. Combination induction of HFD and chemical
HFD is used to induce not only NAFLD but also metabolic syndrome, dyslipidemia, obesity, and insulin resistance (Zhou, Li, et al. Citation2020; Kumar et al. Citation2021; Zheng, Zhu, et al. Citation2021). However, developing the pathological features of T2DM or NASH is a lengthy process. HFD and treatment with various chemicals affecting hepatic physiology in mice or rats accelerated T2DM, NASH, and fibrosis formation. These chemicals included streptozotocin (STZ), tetrachloride (CCl4), diethylnitrosamine (DEN), and thioacetamide (TH). HFD combing with STZ was used to induce T2DM (Zhang et al. Citation2018; Liu, Deng, et al. Citation2019). CCl4 exacerbated hepatocyte ballooning, inflammation, fibrosis stage, ductular reaction, hepatocyte proliferation, and tumor development when mice were fed a western diet (high-fat, high-fructose, and high-cholesterol) (Tsuchida et al. Citation2018). HFD plus CCl4 could induce the NASH model in vivo (Huang, Wu, et al. Citation2021). A hepatocellular carcinoma model was created using DEN (Stowers et al. Citation1988; Jaworski et al. Citation2005; Connor et al. Citation2018). Animal models of NASH induced by HFD combined with DEN contribute to tumor progression (Sylvester Darvin et al. Citation2018; Márquez-Quiroga et al. Citation2022). TH has been widely used to induce acute or chronic liver injury in mice and rats. Fast food diet (FFD) (high saturated fats, cholesterol, and fructose) combined with TH was used to induce NASH and fibrosis (Sharma et al. Citation2019). The combination induction of HFD and chemicals has been listed in .
2.3. Genetic models
The principal genetic animal models of NAFLD are the mice lacking farnesoid X receptor (Fxr-null mice), apolipoprotein E-deficient (ApoE−/−) mice, leptin-deficient (ob/ob) mice, leptin receptor-deficient (db/db) mice, and Zucker fatty rats (fa/fa, ZFR). In hepatic histology, Fxr-null mice exhibited hepatomegaly, hepatic steatosis, and hepatic inflammation (Miyata, Funaki, et al. Citation2020; Miyata, Matsushita, et al. Citation2020). Unlike Fxr-null mice, ApoE-/- mice developed spontaneous hypercholesterolemia and atherosclerosis and were more susceptible to accelerated liver aging and severe liver damage (Hua et al. Citation2021). The strength of the ob/ob and db/db mice was that the phenotype of these mice mimicked the human metabolic syndrome condition in many ways. However, with congenital leptin deficiency and leptin resistance caused by gene mutations, the weakness of these mice was that they didn’t spontaneously develop steatohepatitis or liver fibrosis (Takahashi et al. Citation2012). In rats, the ZFR was the most commonly used genetic model of NAFLD. The ZFR was widely used as an animal model for genetic obesity, insulin resistance, and metabolic syndrome (Matsumoto et al. Citation2021). Genetic models of NAFLD have been listed in .
3. The alteration of phase I DMEs in NAFLD and metabolic comorbidities
Drug metabolism processes can be classified as phase I and phase II reactions. Phase I reactions, such as oxidation, reduction, and hydrolysis, introduce reactive or polar groups (-OH, -COOH, -NH2, -SH, etc.) into drugs. This process is primarily mediated by the CYP450 enzymes, which are mainly oxidases, reductases, and hydrolases. The CYP450 genes are mainly divided into the CYP1, CYP2, and CYP3 subfamilies and are responsible for the metabolism of approximately 73% of clinical drugs, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 (Zhao et al. Citation2021).
Numerous animal studies have observed significant hepatic DMEs changes in NAFLD and metabolic comorbidities. The details and results of these studies have been presented in the following tables ( and ). CYP1A2, a member of the CYP1 family, is exclusively expressed in the human liver (Faber et al. Citation2005). It is responsible for the metabolism of 9% of the drugs used today (Zhao et al. Citation2021), and it can convert some polycyclic aromatic hydrocarbons into carcinogenic intermediates (Vogel et al. Citation2020). CYP2 is the largest family of CYPs, and CYP2D6 and CYP2C19 are responsible for the metabolism of about 27% of the 248 drugs (Zhao et al. Citation2021). Studies have shown that the other isoforms of the CYP2 family have the following rank order in terms of the total hepatic CYP enzyme content: CYP2E1 > CYP2C9 > CYP2D6 > CYP2A6 > CYP2C19 > CYP2B6 (Song et al. Citation2021). The majority of NAFLD animal models showed that the expression and activity of CYP1A2, CYP2C19, and CYP2D6 were inhibited. Results from different adipomorphic rat and ob/ob mouse models showed that the mRNA expression, protein level, and activity of Cyp1a2 were significantly down-regulated (Osabe et al. Citation2008; Lee et al. Citation2013; Chang et al. Citation2014; Li, Clarke, et al. Citation2017; Li et al. Citation2021; Wu et al. Citation2023). However, the mRNA expression of Cyp1a2 in C57BL/6 mice fed with the HFHSD or HFD was up-regulated (Chiba et al. Citation2016; Wang et al. Citation2020). The mRNA expression alteration of Cyp1a2 in NAFLD was not entirely consistent between C57BL/6 mice and ob/ob mice. In HFD-induced obese rats, the mRNA expression, protein level, and activity of CYP1A2 were all down-regulated (Zhang et al. Citation2019). The altered expression trend of CYP1A2 in obesity is consistent with those in HFD rats. It was also found that the expression of CYP1A2 decreased in hypertension and hypercholesterolemia rat models (Niu et al. Citation2022; Xu et al. Citation2022). In contrast, the mRNA expression and activity of CYP1A2 were up-regulated in T2DM rats (Wang et al. Citation2018; Yao et al. Citation2020). The activity of CYP1A2 and CYP2C19 decreased in adults with NASH (Fisher et al. Citation2009; Li, Canet, et al. Citation2017). While both the mRNA expression and activity of Cyp2c29/CYP2C19 were all up-regulated in CDAHFD mice (Suzuki et al. Citation2020). And the protein expression and activity of Cyp2c29 (homologues human CYP2C19) (Li, Clarke, et al. Citation2017), Cyp2d22 (homologues human CYP2D6) (Chiba et al. Citation2016) are down-regulated in animal models feeding on HFD or ob/ob mice (Li, Clarke, et al. Citation2017; Wu et al. Citation2023).
Table 2. The alteration of phase I DMEs in NAFLD and metabolic comorbidities.
Table 3. The alteration of phase II DMEs in NAFLD and metabolic comorbidities.
In human and mouse models, the mRNA expression, protein level, and activity of CYP2A6 were all up-regulated (Fisher et al. Citation2009; Li et al. Citation2013; Wang et al. Citation2017; Wang et al. Citation2019). C57BL/6 mice were fed with the HFD for eight weeks, which resulted in significant inhibition of CYP2B6 activity (Wu et al. Citation2023). It was found that both mRNA and protein expression of CYP2C9 were decreased (Li, Clarke, et al. Citation2017). In hypertension rats, the activity of CYP2B6, CYP2D6, and Cyp2c29/CYP2C19 was all decreased (Niu et al. Citation2022). Simultaneously, the same trend was observed in HFD mice. In T2DM, the protein level and activity of Cyp2c29/CYP2C19 were all down-regulated (Yao et al. Citation2019; Kvitne et al. Citation2022). In humans, CYP2B6 and CYP2C9 mRNA expression increased with NAFLD progression, while both the mRNA and protein expression of CYP2E1 tended to decrease with NAFLD progression (Fisher et al. Citation2009). In contrast, the mRNA and protein expression of Cyp2e1 were up-regulated in HFD rats and mice (Zou et al. Citation2006; Li et al. Citation2011; Wang et al. Citation2020; Liu et al. Citation2022). The mRNA expression, protein level, and activity of CYP2E1 were all up-regulated in obesity, dyslipidemia, and metabolic syndrome mice and T2DM rats (Wang et al. Citation2018, Citation2019, Citation2020; Xu et al. Citation2019; Maksymchuk et al. Citation2022). In hypercholesterolemia, the mRNA and protein expression of CYP2E1 was also up-regulated in HFD mice (Wang et al. Citation2020), while both the mRNA expression and activity of CYP2E1 decreased in rats (Xu et al. Citation2022).
CYP3A4 enzyme is responsible for the metabolism of over 50% of the drugs in clinically used drugs and accounts for nearly 22% of the total hepatic CYP enzymes (Song et al. Citation2021). In patients with NAFLD and HFD-fed mice, the mRNA expression, protein level, and activity of CYP3A4 were down-regulated (Wahlang et al. Citation2014; Woolsey et al. Citation2015; Chiba et al. Citation2016; Jamwal et al. Citation2018). The mRNA expression of Cyp3a11 (homologues human CYP3A4) (Chiba et al. Citation2016) was significantly increased in ob/ob mice. However, a significant decrease in protein expression of Cyp3a11/CYP3A4 was observed in ob/ob MCDD-fed mice. In hypertension rats, the activity of Cyp3a11/CYP3A4 was down-regulated (Niu et al. Citation2022). However, the activity of Cyp3a11/CYP3A4 was not consistent in rats with T2DM (Yao et al. Citation2019, Citation2020). The regulation of Phase I DMEs protein expression in NAFLD is the consistent finding. However, the data about mRNA expression and activity of the murine CYP isoforms are not in complete concordance with each other, which may be indicative of the heterogeneity in the regulation mechanisms known for each isoform (Li, Clarke, et al. Citation2017).
4. Effect of NAFLD and metabolic comorbidities on phase II DMEs
Phase II metabolic reactions, also known as binding reactions, are processes in which the products of phase I reactions are coupled to appropriate functional groups to produce water-soluble compounds that contribute to the detoxification of endogenous and exogenous substrates (Pathania et al. Citation2018). UGTs are responsible for the glucuronidation process. These enzymes bind glucuronic acid to small non-polar molecules, producing glucuronides that are usually inactive and water-soluble, thus facilitating their excretion from the body through the urine or feces. At the same time, the activity of the drug is generally reduced. Thus, glucuronidation detoxifies a broad array of exogenous compounds including environmental toxins, carcinogens, and commonly prescribed drugs. The main UGTs involved in the glucuronidation of drugs in the liver, including UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2A3, UGT2B1, and UGT2B7 (Meech et al. Citation2019). In the UGT1 family, UGT1A1 is involved in the glucuronidation of bilirubin (Lévesque et al. Citation2007). Two isozymes, UGT1A4 and UGT1A3, were identified as the principal catalysts of 25-Hydroxyvitamin D3 glucuronidation in the human liver (Wang et al. Citation2014). UGT1A6 has specificity for planar phenols and arylamines (Bock and Köhle Citation2005). UGT1A9 is involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (Gagné et al. Citation2002). In the UGT2 family, UGT2A3 predominantly glucuronidates hyodeoxycholic acid at the 6-hydroxy position (Court et al. Citation2008). Bisphenol A is glucuronidated by UGT2B1 (Yokota et al. Citation1999). UGT2B7 demonstrated the highest catalytic activities for estrogens (Lépine et al. Citation2004). In steatotic livers of ob/ob mice, Ugt1a1, Ugt1a6, Ugt1a9, and Ugt2a3 mRNA expression increased (Xu et al. Citation2012). In male C57BL/6 mice fed with the HFD, the mRNA expression of Ugt1a1 was higher than those with a low-fat diet at 8 and 18 weeks (Wang et al. Citation2020). In the HFHSD rats, consistent with the mRNA expression, the protein expression of Ugt1a1, Ugt1a6, Ugt1a7, and Ugt2b1 were significantly increased, whereas the protein levels of Ugt1a1, Ugt1a7, and Ugt2b1 were decreased in the HFD rats (Osabe et al. Citation2008). The alteration of Ugt1a1 and Ugt2b1 are not entirely consistent in animal models with NAFLD. Interestingly, the mRNA expression, protein expression, and activity of Ugt1a1, Ugt1a6, Ugt1a9, and Ugt2b7 in obesity, T2DM, or dyslipidemia showed down-regulated changes (Li et al. Citation2018; Zhang et al. Citation2019; Xu et al. Citation2022).
GSTs belong to a family of detoxifying enzymes that protect cellular macromolecules from reactive electrophilic reagents and contribute to the removal of toxic compounds from the cell. The GSTs genes expressed in the liver are GSTA1, GSTA2, GSTA4, GSTM1, and GSTM2 (Desmots et al. Citation2002; Kaur et al. Citation2020). GSTA1 favors the formation of the R-GSH conjugate of both prostaglandin A2 and prostaglandin J2. GSTA2 only showed some minor formation of the R-GSH conjugate of prostaglandin J2 (Bogaards et al. Citation1997). GSTA4 possesses high catalytic efficiency toward 4-hydroxynonenal (4-HNE), a cytotoxic end product of lipid peroxidation (Balogh et al. Citation2010). GSTM1 is involved in the biosynthesis of 14, 15-hepoxilins (Brunnström et al. Citation2011). GSTM2 has been shown to protect astrocytes from aminochrome-induced toxicity (Huenchuguala et al. Citation2016). In human and mouse models, the hepatic mRNA expression of GSTA1 was significantly increased (Lee et al. Citation2016; Lee, Park, et al. Citation2020; Xu et al. Citation2021). The mRNA expression of GSTA4 was up-regulated in mice with a high-fat diet (Sharma et al. Citation2018). It was found that GSTM2 mRNA and protein expression markedly decreased in NASH patients. Consistent with the clinical results, the mRNA and protein expression of Gstm2 were also significantly down-regulated in mice after a 24-week HFD, a 16-week HFHCD, or a 4-week MCDD (Lan et al. Citation2022). Moreover, the variation trend of GSTM2 in metabolic syndrome was consistent with that in NAFLD (Carreira et al. Citation2018).
SULTs are cytosolic enzymes that catalyze the sulfonation of endogenous and exogenous compounds by adding a sulfonate fraction to the compound to increase its water solubility and reduce its biological activity. In humans, SULTs are classified into five gene families, SULT1, SULT2, SULT3, SULT4, and SULT6 families (Kurogi et al. Citation2021). SULT1A1 is the main enzyme of SULTs in the liver, followed by SULT2A1, SULT1B1, and SULT1E1 (Riches et al. Citation2009). SULT1A1 sulfonates pro-carcinogens such as hydroxymethyl polycyclic aromatic hydrocarbons (Hempel et al. Citation2007). SULT2A1 is the major hydroxysteroid (alcohol) sulfotransferase, and it catalyzes the 3′-phosphoadenosine-5′-phosphosulfate-dependent sulfation of various endogenous hydroxysteroids as well as many xenobiotics that contain alcohol and phenol functional groups (Gulcan and Duffel Citation2011). SULT1B1 is involved in the sulfation of dotinurad (Omura et al. Citation2021). SULT1E1 plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens (Silva Barbosa et al. Citation2020). In male C57BL/6 mice fed with the HFD, the mRNA expression of Sult1a1 was higher than those with a low-fat diet at 8 and 18 weeks (Wang et al. Citation2020). The study showed that the HFD decreased the Sult1b1 and Sult1e1 mRNA expression in mice (Wang, Tao, et al. Citation2016). However, the protein levels of Sult1e1 were up-regulated in the NAFLD rat model (Cong et al. Citation2021). The species, breeds, and genetic background of the animal models may be the factors that influence gene expression. The mRNA expression of SULT1A1 in rats with T2DM or dyslipidemia was down-regulated (Li et al. Citation2018; Xu et al. Citation2022). And Fashe et al. found the mRNA expression of SULT1E1 in patients with T2DM was up-regulated (Fashe et al. Citation2021). The above studies have reported that the metabolic comorbidities also regulated the expression of phase I/II DMEs and that some of the gene regulation trends are consistent with NAFLD.
5. The alteration of pharmacokinetic parameters in NAFLD
There is a new and more and more frequently applied tendency to use natural products in curing/alleviating NAFLD, such as spirulina, oleuropein, garlic, berberine, resveratrol, curcumin, ginseng, glycyrrhizin, coffee, cocoa powder, epigallocatechin-3-gallate, and bromelain. And many promising drug candidates are present in the current development pipeline that are of natural origin (Tarantino et al. Citation2021). Meanwhile, Chachay et al. speculated that resveratrol kinetics may be altered in NAFLD with obesity, resulting in reduced parent concentration (Chachay et al. Citation2014), which has prompted a movement to consider whether DMEs in NAFLD also affect pharmacokinetic parameters. Although few clinical studies have reported the impact of NAFLD on commonly prescribed drugs and natural products, they strongly emphasize the potential of NAFLD to cause variable drug responses and adverse drug reactions through altering pharmacokinetic parameters (Cobbina and Akhlaghi Citation2017). A limited number of pharmacokinetic studies are currently available on NAFLD. shows the substrates and pharmacokinetic parameters of the major DMEs whose expression was altered under the pathological conditions of NAFLD.
Table 4. Pharmacokinetic changes of drugs in NAFLD.
Clozapine, the substrate of CYP1A2, is an atypical antipsychotic. It is mainly used for the treatment of bipolar disorder and schizophrenia (Nucifora et al. Citation2017; Delgado et al. Citation2020). The main metabolite of clozapine is norclozapine. Norclozapine is a pharmacologically active compound and has more metabolic side effects than clozapine. In orotic acid diet (OAD) rats, consistent with previous reports, the hepatic protein expression of CYP1A2 was down-regulated, resulting in a significant increase in the area under curve (AUC) and AUCnorclozapine/AUCclozapine ratios of norclozapine. In addition, higher steady-state brain concentrations of clozapine and norclozapine were observed in OAD rats. These results suggested that caution may be warranted in the use of clozapine in patients with preexisting or drug-induced NAFLD (Li et al. Citation2021).
Caffeine is a naturally occurring stimulant found in coffee, tea, and chocolate. And it is used as an additive in other beverages and adjuvant analgesic in some pain medications (Mandel Citation2002; Sawynok Citation2011). Systemic caffeine clearance is considered the gold standard for phenotyping CYP1A2 in epidemiological studies. And the measurement of a unique salivary caffeine concentration has been recommended for verifying the presence and eventually the type of compensated liver cirrhosis. The results demonstrated that the salivary pharmacokinetics of caffeine in cirrhotic patients is very prolonged with respect to the findings of a previous study carried out in healthy subjects in which the mean serum half-life of caffeine was found to be very short. (Tarantino et al. Citation2006). Omeprazole, a proton pump inhibitor, is used to treat patients with erosive esophagitis who have gastroesophageal reflux disease (Richter et al. Citation2001). In ob/ob and ob/ob MCDD mice, the hepatic mRNA expression and protein levels of Cyp1a2, and Cyp2c29 (homologues human CYP2C19) were significantly decreased. Furthermore, the pharmacokinetics of caffeine and omeprazole, the probe drugs of Cyp1a2 and Cyp2c29, were significantly changed. The maximum concentration (Cmax) and the AUC of caffeine were significantly increased, while the AUCmetabolite/AUCdrug ratio of caffeine and omeprazole was significantly decreased in ob/ob mice, and ob/ob MCDD mice (Li, Clarke, et al. Citation2017). Consistently, in NASH adults and adolescents, the activity of CYP2C19 was a significant decrease. And the metabolic AUC ratio of omeprazole was decreased by 71% in NASH adolescents (Li, Canet, et al. Citation2017). These results revealed that plasma concentrations of caffeine and omeprazole are higher in patients with NAFLD at the same dose. It is unclear whether higher plasma concentrations of caffeine and omeprazole in patients with NAFLD at the same dose affect the adverse effects and clinical efficacy. And more objective and rigorous studies are required to determine whether the dosage of these two drugs can be adjusted in the NAFLD population.
Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions (Nielsen et al. Citation2016), and it is a selective probe of CYP2E1 activity in vivo. It was found that the metabolic clearance of chlorzoxazone was markedly elevated in obese subjects with NASH than those without NASH (Emery et al. Citation2003). Midazolam is a short-acting benzodiazepine that is widely used as a premedicant prior to surgery, for induction of anesthesia, and for conscious sedation (Rodolà Citation2006). The CYP3A4 protein expression levels were significantly lower in patients with NAFLD and NASH. Compared with control subjects, midazolam concentrations were significantly higher in human subjects with NASH (Woolsey et al. Citation2015; Jamwal et al. Citation2018). In the HFD-fed mice model, both mRNA and protein expression levels of Cyp3a11/CYP3A4 tended to decrease. What’s more, HFD mice had significantly prolonged sleeping times after midazolam (Cyp3a11/CYP3A4 substrate) (Ghose et al. Citation2011). The results led us to wonder whether current drug dosage recommendations may need to be reevaluated in the NAFLD population to ensure the premier clinical outcomes of these drug therapies.
6. Future perspectives and conclusion
In conclusion, DMEs (phase I and II DMEs) play an important role in the metabolism of drugs. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. The data of enzymatic activity, mRNA expression, and protein expression of the CYP isoforms are not in complete concordance with each other, which may be indicative of the heterogeneity in the regulation mechanisms known for each isoform. In addition, the species, breeds, and genetic background of the animal models may be the factors that influence gene expression. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated in the NAFLD population to avoid serious adverse effects in patients with NAFLD. However, most studies about the alteration of pharmacokinetic parameters have been conducted in rodents. Therefore, the clinical applicability of the pharmacokinetic data is limited. More objective and rigorous studies are required to confirm these pharmacokinetic changes in patients with NAFLD and determine whether these pharmacokinetic changes affect drug dosage recommendations in the NAFLD population. At present, we have also summarized the substrates of the DMEs aforementioned to provide future research direction in . Thus, future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD.
Table 5. List of well-known substrates for phase I and II DMEs.
Author contributions
Yan Zhu: Conceptualization, Writing- Reviewing and Editing. Li Chen: Investigation, Writing—Original Draft preparation. Yan Zhu and Li Chen had the same contribution to this work. Yuqi He: Supervision. Lin Qin: Visualization. Daopeng Tan: Visualization. Zhaojun Bai and Yu Song: Methodology. Yuhe Wang: Supervision and Project administration. All authors contributed to the article and approved the submitted version.
Disclosure statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
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