Roles of cytochrome P450 enzymes and their blockers in cancer and other human diseases

Various types of enzymes orchestrate a broad range of metabolic processes in organisms, including humans. Enzyme inhibitors bind enzyme active sites to modulate their catalytic activity, offering potential treatments for diverse diseases (Copeland et al. 2007). The clinical use of numerous enzyme inhibitors underscores the importance of enzymes as viable drug targets (Copeland 2005). Several key enzymes involved in cellular and drug metabolism have emerged as promising therapeutic targets for diseases with limited effective treatment options (Robertson 2005; Orhan 2019; Zhao et al. 2021).

Translational cancer research has shifted from conventional cytotoxic chemotherapy toward targeted prodrug approaches to improve anticancer drug efficacy (Yang et al. 2020; Lee et al. 2024). This strategy exploits unique patterns of CYP expression and activity to enhance the precision and effectiveness of cancer treatments (Singh et al. 2023).

Additionally, CYPs are implicated in the pathogenesis of non-neoplastic diseases. In the liver, CYP-mediated drug metabolism generates toxic metabolites that cause hepatotoxicity (Wu et al. 2017; Shin et al. 2023). In cardiovascular tissues, including the heart, endothelium, and vascular smooth muscle, CYPs contribute to cardiovascular homeostasis by metabolizing endogenous compounds, such as epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), prostaglandins, aldosterone, and sex hormones. Their activity correlates with various cardiovascular diseases, including hypertension, stroke, and arrhythmia (Elbekai and El-Kadi 2006). Hence, targeting CYPs has emerged as a novel drug discovery approach, with ongoing investigations into CYP inhibition and induction by established drugs.

Drugs interact with the CYP system via inhibition or induction (Hakkola et al. 2020). Inhibitors reduce CYP metabolic activity, depending on dosage and enzyme-binding capacity (Lynch and Price 2007). Certain drugs are metabolized or inhibited by the same enzyme, while others are metabolized by one enzyme and inhibited by another (Kotlyar et al. 2005). Clinically, drug combinations may exploit CYP inhibition for therapeutic benefit (Ramanarayanan and Scarpace 2007; Guo et al. 2018). Modulating CYP activity leads to clinically relevant drug–drug interactions (DDIs), causing unexpected adverse reactions or altered therapeutic effects (Scott and Halpert 2005; Lynch and Price 2007; Hakkola et al. 2020).

Reversible CYP inhibitors disrupt the catalytic cycle before forming activated oxygen intermediates. Conversely, inhibitors acting during or after the formation of activated oxygen intermediates are classified as quasi-irreversible or irreversible (Kamel and Lamsabhi 2020). Reversible CYP inhibition is considered the primary mechanism underlying DDIs (Hollenberg 2002). Assessing the consequences of the interactions between CYP inhibitors and drugs metabolized by targeted CYPs has substantial clinical relevance (Kilford et al. 2022).

Therefore, this review aims to examine the roles of CYP isoforms in various diseases, including cancer, and their significance in drug development. Further, Food and Drug Administration (FDA)-approved CYP inhibitors and recent advancements in novel inhibitor research are discussed. The findings could provide a comprehensive understanding of CYP-targeted therapies and their clinical applications.

Histamine is crucial in regulating numerous physiological processes, including cell proliferation, differentiation, hematopoiesis, embryonic development, tissue regeneration, and wound healing. It acts through multiple receptor subtypes, particularly the H₁ receptor, which rapidly affects vascular endothelial, bronchial, and smooth muscle cells. Consequently, acute manifestations such as rhinitis, bronchoconstriction, spasms, diarrhea, and skin reactions can occur (Jutel et al. 2009).

H1-antihistamines, including promethazine, chlorpheniramine, tripelennamine, diphenhydramine, and cyclizine, mitigate histamine-induced responses through H₁ receptor blockade. These drugs inhibit CYP2D6 or CYP2C9 (He et al. 2002). An in vitro assay using human liver microsomes demonstrated strong inhibition of the bufuralol 1'-hydroxylation activity of CYP2D6 by these H1-antihistamines. Promethazine and chlorpheniramine exhibit competitive inhibition at concentrations approximating therapeutic plasma levels. In contrast, only cyclizine and promethazine inhibited tolbutamide 4-methylhydroxylation activity mediated by CYP2C9 (He et al. 2002).

CYP2B6 is essential in the hydroxylation of the antidepressant bupropion. In vitro studies demonstrate that cetirizine, chlorpheniramine, desloratadine, fexofenadine, hydroxyzine, loratadine, olopatadine, and terfenadine inhibit CYP2B6-mediated bupropion hydroxylation (Walsky et al. 2006). Moreover, loratadine and terfenadine inhibit the N-deethylation of the antimalarial drug amodiaquine, a surrogate marker reaction commonly used to assess CYP2C8 activity in vitro (Lai et al. 2009). These findings underscore the potential for DDIs between antihistamines and the metabolism of bupropion or amodiaquine.

CYP1A2 metabolizes caffeine into primary metabolites, including theophylline. Consequently, CYP1A2 polymorphisms can alter the metabolism and clearance of theophylline (Obase et al. 2003). Furafylline, a theophylline alternative, acts as a potent and selective inhibitor of CYP1A2 (Guo et al. 2021). Inhibition of CYP1A2 by furafylline reduces the oxidation of caffeine, leading to higher plasma caffeine levels (Wójcikowski and Daniel 2009). Similarly, concurrent administration of theophylline and furafylline suppresses the formation of theophylline metabolites, 1-methylxanthine and 1,3-dimethyl uric acid, which may affect the clinical efficacy of theophylline (Lee et al. 2014). These findings underscore the importance of considering potential DDIs in asthma therapy to optimize treatment efficacy and patient safety.

Zafirlukast, a leukotriene receptor antagonist used in asthma treatment, is primarily metabolized by CYP2C9 and CYP3A4. Consequently, genetic polymorphisms in CYP2C9 influence the biotransformation of zafirlukast (Lee et al. 2016). Zafirlukast inhibits tolbutamide 4-methylhydroxylation along with the 1-hydroxylation of midazolam, indicating its function as a CYP2C9 and CYP3A4 inhibitor, respectively (Liu et al. 2004a, b). Zafirlukast also acts as a minor inhibitor of S-mephenytoin 4'-hydroxylation catalyzed by CYP2C19, phenacetin O-deethylation (CYP1A2), and dextromethorphan O-demethylation (CYP2D6) (Liu et al. 2004a, b). Montelukast, another leukotriene receptor antagonist, serves as a potent competitive inhibitor of CYP2C9 and CYP2C8, suppressing CYP2C8-catalyzed amodiaquine N-deethylase activity (Lai et al. 2009). Pranlukast, a structural analog of zafirlukast, competitively inhibits CYP2C9 and moderately suppresses tolbutamide hydroxylation (Liu et al. 2004a, b).

Tuberculosis, a major global public health concern and leading cause of mortality from infectious diseases, is often associated with latent infections induced by Mycobacterium tuberculosis in humans. Antibiotics, particularly isoniazid, are vital in preventing and treating tuberculosis (Lobue and Moser 2003). In vitro studies examining the inhibitory effect of isoniazid on CYP activity in human liver microsomes demonstrated notable inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. Specifically, isoniazid exhibits reversible inhibition of CYP2C19 and CYP3A4 activity (Wen et al. 2002). Beyond reversible inhibition, in which enzyme activity is directly impeded, CYPs can also undergo metabolic or mechanism-based inhibition. In vitro, isoniazid exhibits differential inhibition of CYP enzymes depending on the presence of NADPH. In the absence of NADPH, isoniazid acts as a competitive inhibitor of CYP1A2, CYP2C9, and CYP2E1; a mixed-type inhibitor of CYP2A6, CYP2C19, and CYP2D6; and an uncompetitive inhibitor of CYP3A4. However, in the presence of NADPH, isoniazid exhibits mixed-type inhibition of CYP1A2 and CYP2C19, noncompetitive inhibition of CYP2A6, and uncompetitive inhibition of CYP3A4. Therefore, the concurrent administration of isoniazid with drugs primarily metabolized by CYP2C19 and CYP3A4 may lead to significant DDIs, with potentially serious clinical implications (Wen et al. 2002; Zhou and Zhou 2009).

Erythromycin, a widely used macrolide antibiotic, acts as a mechanism-based inhibitor of CYP enzymes, with specific activity against CYP3A4 (Zhou 2008). Following erythromycin binding, the flexible active site of CYP3A4 undergoes significant conformational changes that increase its volume. Given that CYP3A4 mediates the metabolism of most drugs, the investigation of DDIs involving erythromycin and its substrates is crucial. For example, palbociclib, a CDK4/6 inhibitor metabolized by CYP3A4, exhibits significant pharmacokinetic alterations when co-administered with erythromycin. These findings underscore the importance of clinical evaluation and appropriate dose adjustments (Molenaar-Kuijsten et al. 2022).

Quinolones inhibit CYP1A2, the enzyme responsible for catalyzing caffeine 3-demethylation. Certain quinolone antibiotics containing the 4-oxoquinoline-3-carboxylic acid as a core structure competitively inhibit caffeine 3-demethylation (Zhou et al. 2010). Additionally, ciprofloxacin exhibits weak inhibitory activity against CYP1A2 and CYP2C9, while levofloxacin only inhibits CYP2C9 (Zhang et al. 2008).

Cushing's syndrome (CS) is a rare disorder, with an annual incidence of approximately 1.8–3.2 cases per million individuals, but it can be life-threatening owing to prolonged exposure to glucocorticoids. This exposure leads to a wide range of comorbidities, including cardiovascular, metabolic, dermatological, neuropsychiatric, musculoskeletal, and reproductive symptoms (Fleseriu and Castinetti 2016; Hakami et al. 2021). Endogenous CS is classified into adrenocorticotropic hormone (ACTH)-dependent (70–80%) and ACTH-independent forms (Ma et al. 2016). Among ACTH-dependent CS cases, 80–90% arise from corticotroph pituitary adenomas (Cushing's disease or corticotropinoma), representing approximately 65% of all CS cases, while the remaining 10–20% result from ectopic ACTH-secreting tumors (Ma et al. 2016; Gadelha et al. 2023). Transsphenoidal surgery is the first-line treatment for CS, with appropriate biochemical control of hypercortisolism to prevent disease recurrence. Medical therapy is classified into three categories: adrenal steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate), pituitary tumor-directed agents (cabergoline and pasireotide), and glucocorticoid receptor antagonists (mifepristone) (Gadelha et al. 2023). Steroidogenesis inhibitors reduce cortisol production by targeting specific enzymes: CYP11A1 (ketoconazole and etomidate), CYP11B1 (ketoconazole, levoketoconazole, metyrapone, mitotane, etomidate, and osilodrostat), CYP11B2 (ketoconazole, metyrapone, mitotane, and osilodrostat), CYP17 (ketoconazole, metyrapone, and etomidate), and CYP19 (ketoconazole, levoketoconazole, and metyrapone) (Gadelha et al. 2023; Cai et al. 2022).

Fluvoxamine, a selective SSRI, is a potent inhibitor of CYP1A2, which is responsible for the N3-demethylation of caffein and theophylline, and phenacetin O-deethylation (Luong et al. 2022; Ma et al. 2025a, b). Consequently, fluvoxamine may alter the metabolism of CYP1A2 substrate drugs (Britz et al. 2019).

Most antidepressants are metabolized primarily by CYP2D6 (Haufroid and Hantson 2015). Paroxetine, a substrate of this enzyme, acts as a potent inhibitor of CYP2D6, hindering the metabolic clearance of desipramine, a tricyclic antidepressant generated from imipramine via CYP2C19. Consequently, co-administration of desipramine with paroxetine necessitates a substantial dosage reduction (Zakaraya et al. 2024). Furthermore, bupropion—a CYP2B6 substrate—and its metabolite hydroxybupropion inhibit CYP2D6, thereby reducing desipramine metabolism. Hence, caution is required when administering desipramine (Kotlyar et al. 2005).

Lesinurad, a uricosuric drug used in the treatment of gout, is primarily metabolized by CYP2C9. Genetic polymorphisms in CYP2C9 can increase plasma concentrations of lesinurad. Therefore, caution is warranted when co-administering CYP2C9 inhibitors with lesinurad, as they may affect its metabolism and further elevate plasma drug levels (Dean 2012). Lesinurad may act as a weak inhibitor of CYP2C9 (Shen et al. 2019). However, this inhibitory effect is negligible, allowing the substrates of the CYP2C9 enzyme to be significantly affected during metabolic processes by benzbromarone, a potent inhibitor of CYP2C9 (Locuson et al. 2003).

Benzbromarone, a uricosuric agent, inhibits CYP2C9 and CYP3A4. In particular, it structurally inactivates CYP3A4 through irreversible covalent adduction. This can result in clinically significant DDIs and is linked to benzbromarone-induced fatal hepatotoxicity (Masubuchi and Kondo 2016; Tang et al. 2021).

In premenopausal women, estrogen plays a key role in increasing high-density lipoprotein levels while lowering low-density lipoprotein (LDL) and triglyceride levels, thereby reducing the risk of hyperlipidemia compared with men of the same age. CYP2C9 contributes to the metabolism of estrogens, including estradiol, estrone, and progesterone. Consequently, genetic polymorphisms in CYP2C9 may alter estrogen concentrations and contribute to the development of hyperlipidemia (Luo et al. 2005). Gemfibrozil, which is used to treat hyperlipidemia by lowering LDL and triglyceride levels, is a potent inhibitor of CYP2C8 and CYP2C9 (Wen et al. 2001; Davidson 2006). In vitro, gemfibrozil only weakly inhibits CYP2C8. However, once glucuronidated to form its metabolite, gemfibrozil 1-O-β-glucuronide, it becomes a significant CYP2C8 inhibitor in vivo (Tornio et al. 2017).

A study on using pooled human liver microsomes demonstrates that gemfibrozil is a potent, competitive inhibitor of CYP2C9. This suggests that gemfibrozil may interact with CYP2C9 substrate drugs such as warfarin or glyburide (Wen et al. 2001). Additionally, co-administration of cerivastatin, a cholesterol-lowering statin, with gemfibrozil, a CYP2C8 inhibitor, interferes with the production of the hydroxy metabolite of cerivastatin. These findings highlight the importance of considering potential DDIs when prescribing gemfibrozil with other CYP2C8-metabolized medications (Wang et al. 2002).

CYP enzymes metabolize arachidonic acid in the brain and blood vessels to generate metabolites such as EETs, dihydroxyeicosatrienoic acids (DiHETEs), and HETEs. These metabolites are crucial in cardiovascular diseases, including hypertension (Sarkis and Roman 2004). Meanwhile, increasing research efforts have focused on investigating CYP inhibition by existing antihypertensive drugs.

Diltiazem, a calcium channel blocker widely prescribed for hypertension and angina, is primarily metabolized by CYP3A4 (Zisaki et al. 2015). Diltiazem is a moderate CYP3A4 inhibitor, but its metabolites, N-desmethyldiltiazem and N,N-didesmethyldiltiazem, are very strong reversible inhibitors of CYP3A. Consequently, prolonged exposure to diltiazem in humans causes these metabolites to accumulate in the blood, which further inhibits CYP3A4 and reduces diltiazem clearance (Zhao 2008; Byeon et al. 2018). Given the central role of CYP3A4 in metabolizing numerous drugs, characterizing interactions between diltiazem and other CYP3A4 substrates is of considerable interest. For example, in a study involving 10 healthy volunteers, co-administering simvastatin—a cholesterol-lowering drug metabolized by CYP3A4—and diltiazem resulted in a significant interaction, underscoring the need for caution when prescribing simvastatin with diltiazem or other CYP3A4 inhibitors (Mousa et al. 2000).

Antimalarial drugs, including hydroxychloroquine, are primarily metabolized in the liver by CYP2D6, CYP3A4, and CYP2C8 (Rendic and Guengerich 2020). Genetic polymorphisms in these enzymes can significantly influence drug metabolism (Elewa and Wilby 2017). Chloroquine has been reported to suppress CYP2D6 activity, potentially through autoinhibition of its own metabolism. Consistently, hydroxychloroquine, its less toxic derivative, has also been shown to significantly inhibit this enzyme, suggesting that both agents may impact the metabolism of CYP2D6 substrates (Chamboko et al. 2023; Paludetto et al. 2023). When co-administering CYP2D6 inhibitors with other therapies to treat malaria or other inflammatory diseases, evaluating potential DDIs is essential, as they may affect the metabolism of CYP2D6 substrates (Rendic and Guengerich 2020).

The antifungal drugs ketoconazole, fluconazole, voriconazole, and itraconazole are potent inhibitors of CYP3A4 (Guengerich 2022), as demonstrated in studies of testosterone metabolism. Ketoconazole, voriconazole, and fluconazole exhibit comparable inhibitory effects, while itraconazole produces distinct effects, potentially due to its larger molecular size, which enables tighter binding to the CYP3A4 catalytic site (Yamaguchi et al. 2021). Ketoconazole is a strong CYP3A inhibitor that effectively hinders the biotransformation of CYP3A substrates (Greenblatt et al. 2011; Yamaguchi et al. 2021), with its inhibitory potency varying in a substrate-dependent manner (Greenblatt et al. 2011). Fluconazole also inhibits CYP2C9 and CYP2C19, resulting in DDIs that enhance the anticoagulant effects of warfarin (Akamatsu et al. 2023).

The antifungal agent terbinafine acts as a CYP2D6 inhibitor and induces a discrepancy between the genotype and phenotype of the enzyme. Consequently, concomitant administration of terbinafine may significantly influence the biotransformation of CYP2D6 substrates (Nahid et al. 2025).

Polymorphisms in CYP2C19 are associated with peptic ulcer disease (Sychev et al. 2015). The distribution of CYP2C19 genotypes varies among patients with gastrointestinal disease, and rapid metabolizer genotypes may increase susceptibility to peptic ulcer disease and gastrointestinal bleeding (Jainan and Vilaichone 2014). Helicobacter pylori (H. pylori) infection significantly increases the risk of peptic ulcers, gastritis, and gastric cancer (Liou et al. 2024). Therefore, eradicating H. pylori is a key component of treatment strategies for patients with peptic ulcer disease (Kurzawski et al. 2006). Proton pump inhibitors (PPIs) are commonly used in H. pylori eradication therapy, with CYP2C19 playing a crucial role in their metabolic processing. Thus, PPI metabolism is influenced by CYP2C19 polymorphisms, which influence treatment outcomes in patients with peptic ulcer disease (Klotz et al. 2004; Kurzawski et al. 2006).

Several PPIs that serve as CYP2C19 substrates also function as inhibitors of the same enzyme. For example, esomeprazole and omeprazole are clinically potent inhibitors of CYP2C19 (Zvyaga et al. 2012). In vitro, esomeprazole shows time-dependent inhibition of CYP2C19, with higher doses producing stronger inhibitory effects (Kaartinen et al. 2020). Additionally, omeprazole and its metabolites reversibly inhibit CYP2C19, and DDIs involving other CYP2C19 substrates are well documented (Malling et al. 2005).

Cimetidine is the first FDA-approved histamine H₂-receptor antagonist that effectively inhibits gastric acid secretion (Khawaja et al. 2024). It is also a well-recognized inhibitor of CYP2C19 and other CYP enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5 (Malling et al. 2005; Guengerich 2022). Patients undergoing treatment with drugs metabolized and deactivated by CYP3A4 may experience enhanced drug effects due to pharmacokinetic interactions when co-administered with cimetidine, a competitive inhibitor for CYP3A4 (Wendl et al. 2022).

Psoriasis is recognized as a chronic autoimmune skin condition accompanied by systemic inflammation, exerting wide-ranging effects that extend beyond the skin and influence cardiometabolic, renal, malignant, and psychological health (Bu et al. 2022). CYPs play significant roles in the pathogenesis of various skin diseases (Chen et al. 2024a, b). CYP2S1 may contribute to psoriasis development by inhibiting keratinocyte proliferation and regulating immune response pathways (Sheng et al. 2021).

Methoxsalen, a natural coumarin which is a well-known medication for psoriasis, functions as a potent therapeutic agent for lung cancer through selective inhibition of CYP2A6 and CYP2A13 (Sharma et al. 2024). CYP2A6 metabolizes nicotine into cotinine, thereby influencing smoking behaviors and lung cancer risk. Methoxsalen can potentially reduce smoking behavior in vivo by inhibiting CYP2A6-mediated nicotine metabolism (Zhang et al. 2001; Zhu et al. 2013). Furthermore, methoxsalen is a potent inhibitor of CYP1A2, markedly reducing phenacetin O-deethylation activity (Palacharla et al. 2019).

The metabolism of most antipsychotic medications depends on various CYP isoforms, rendering them susceptible to alterations when subjected to antipsychotics capable of concurrently inhibiting CYPs (Basińska-Ziobroń et al. 2025). Olanzapine, commonly prescribed for schizophrenia and related conditions, is primarily metabolized by CYP1A2. Consequently, fluvoxamine—a CYP1A2 inhibitor—significantly increases the peak plasma concentrations and reduces the clearance of clozapine and olanzapine, indicating that lower doses of the second-generation antipsychotics may be required to maintain therapeutic levels when co-administered with fluvoxamine (Lenze et al. 2022; Mahgoub et al. 2023).

Several antipsychotic drugs––including chlorpromazine, fluphenazine, haloperidol, perphenazine, and thioridazine––have been identified as CYP2D6 inhibitors (DeBattista and Schatzberg 2024; Basińska-Ziobroń et al. 2025). Studies assessing the inhibition of bufuralol 1′-hydroxylation and codeine O-demethylation, a CYP2D6-mediated reaction, demonstrate competitive inhibition (Vevelstad et al. 2009; Wójcikowski et al. 2020). Among these, thioridazine and perphenazine exhibited the greatest potency with K_i values of 1.4 and 0.8 μM, respectively (Basińska-Ziobroń et al. 2025). Moreover, fluphenazine and perphenazine moderately inhibit CYP1A2-mediated phenacetin O-deethylation (Daniel et al. 2001).

When CYP enzymes metabolize arachidonic acid, they produce eicosanoids that regulate cerebral blood flow. CYP-mediated eicosanoid-induced cerebrovascular dysfunction plays a significant role in stroke development and progression (Huang et al. 2016). Additionally, polymorphisms in the CYP promoter increase ischemic stroke risk. A clinical trial involving 121 patients with ischemic stroke reports associations between nucleotide polymorphisms in CYP11B2, CYP2E1, and CYP7A1 and the occurrence of ischemic stroke (Kim et al. 2012). Another trial involving patients with ischemic stroke and carotid stenosis shows that CYP polymorphisms alter plasma levels of CYP-derived metabolites, including EETs, DiHETEs, and HETEs, which increase the risk of carotid stenosis (Yi et al. 2016). These findings highlight the importance of considering CYP inhibition as a potential strategy in stroke treatment.

Ticlopidine, an antiplatelet drug commonly used in managing thrombotic stroke, inhibits CYPs. In vitro studies using human liver microsomes report ticlopidine as a potent competitive inhibitor of CYP2C19 and CYP2D6. It also inhibits CYP1A2 and CYP2C9 (Ko et al. 2000). Clopidogrel, another thienopyridine antiplatelet agent, inhibits CYP2C8, with significant implications for studies evaluating the effects of co-administering CYP2C8 substrates (Axelsen et al. 2021). Additionally, ticlopidine and clopidogrel exhibit mechanism-based inhibition of CYP2B6, characterized by time- and concentration-dependent, irreversible NADPH-dependent inhibition (Richter et al. 2004).

Several antiretroviral drugs used for managing HIV/AIDS are CYP inhibitors (Gong et al. 2019). These drugs are often administered in combination therapy to target different stages of the HIV life cycle and slow disease progression (De Clercq 2009). Ritonavir and cobicistat, potent CYP3A4 inhibitors, mitigate the need for higher doses and frequent administration of CYP3A4-metabolized antiretroviral drugs (Gong et al. 2019). Furthermore, ritonavir has more recently been repurposed to treat COVID-19 (Meini et al. 2020). Paxlovid, a combination of ritonavir and nirmatrelvir, was the first FDA-approved oral treatment for COVID-19 granted Emergency Use Authorization (Saheb Sharif-Askari et al. 2024). Nirmatrelvir inhibits the 3-chymotrypsin-like cysteine protease of SARS-CoV-2, while ritonavir enhances its antiviral effect by interfering with CYP3A4-induced metabolism of nirmatrelvir (Amani and Amani 2023). Clinical inhibition of CYP3A4 by ritonavir is characterized according to its nearly irreversible nature, requiring new enzyme synthesis for functional recovery (Loos et al. 2022). Additionally, ritonavir inhibits CYP2C8 and CYP2D6 (Lai et al. 2009; Guengerich 2022).

Antiretroviral medications exhibit complex interactions with CYP metabolic pathways. For instance, efavirenz is primarily metabolized by CYP2B6 and concurrently inhibits CYP1A2, CYP2C9, and CYP3A4. Similarly, etravirine is metabolized by CYP3A4, CYP2C9, and CYP2C19, while also inhibiting CYP2C9 and CYP2C19 (Stolbach et al. 2015; Gong et al. 2019). Moreover, retroviral protease inhibitors, such as atazanavir, darunavir, fosamprenavir, lopinavir, saquinavir, indinavir, and nelfinavir, generally exert intermediate to weak inhibitory effects on CYP3A4. Conversely, tipranavir specifically inhibits CYP2D6 (Gong et al. 2019).

Recognizing the significance of disease-causing CYP metabolites has driven active research into developing drugs that target and inhibit CYP enzymes. Earlier studies primarily focused on evaluating the potency and mechanisms of action of existing CYP inhibitors. More recently, advances in structural analyses have offered comprehensive insights into why several current CYP inhibitors lack selectivity. This knowledge supports the rational design of highly selective CYP inhibitors with potential for targeted therapeutic interventions (Zhao et al. 2019). For example, studies show the efficacy of CYP1A inhibitors in cell-based assays, suggesting potential for developing selective inhibitors for other CYP isoforms (Dai et al. 2024).