Introduction

The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (Coronaviridae Study Group of the International Committee on Taxonomy of Viruses 2020), has resulted in approximately 18.3 million infectees and 24,488 deaths in Korea and 541 million infectees/6.32 million deaths worldwide (Our World in Data, accessed on 22 June 2022) since the first outbreak occurred in Wuhan on 1 December 2019 (Ritchie et al 2021). The disease presents as acute respiratory distress (ARD) and can develop into fatal systemic manifestations (extrapulmonary as well as pulmonary) and premature mortality (Yan et al. 2020; Gupta et al. 2020). Clinical management of COVID-19 patients is focused on improving symptoms, supporting lung function, remedying acute inflammation (cytokine storm), and preventing infection (Yan et al. 2020).

SARS-CoV-2, the novel coronavirus (65–125 nm in size), an enclosed and single-stranded positive-sense ribonucleic acid (RNA) (26–32 kbs) virus (Fig. 1a), belongs to the genus Beta-coronavirus, like SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) (Zhang and Holmes 2020; Shereen et al. 2020). SARS-CoV-2 has a similar infection cycle to SARS-CoV and MERS-CoV (V’Kovski et al. 2021), as shown in Fig. 1b. The spike glycoprotein (S-gp) of the virus binds to the human cell membrane receptor angiotensin-converting enzyme 2 (ACE2) and cell entry is enabled by priming of the S-gp by the cellular transmembrane serine protease 2 (TMPRSS2) (Hoffman et al. 2020). Once the host cell is entered, the viral infection cycle proceeds with replication of the nucleocapsid (N), envelope (E), membrane (M), S-gp proteins, RNA-dependent RNA polymerase, 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), and the RNA genome; followed by assembly; and exocytosis of mature SARS-CoV-2. Viral infection induces pathology in the respiratory tissue, liver, intestine, and kidney, among other locations, through viral toxicity, endothelial cell damage, and immunological/inflammatory responses (Gupta et al 2020; Chen et al. 2021a). Although the mechanism of COVID-19 pathology is not fully understood, potential clinical targets have been explored for pharmacological, immunological, and molecular approaches (Chen et al. 2021a; Ghareeb et al. 2021) (Fig. 1b). The pharmacological approach to COVID-19 therapy covers most steps of the viral infection cycle (cell entry, replication of proteins and genomic RNA, and assembly), while immunological approaches (antibodies and vaccines) mainly focus on the initial step (cell entry) (Fig. 1b).

Fig. 1
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SARS-CoV-2 infection. a SARS-CoV-2 structure. S-gp, spike glycoprotein; M, membrane protein; E, envelope protein; N, nucleocapsid protein. b Viral infection cycle and molecular interventions are comprised of cell entry, host cell entry by endocytosis or membrane fusion; Replication (of viral proteins and genomic RNA); Assembly; Exocytosis (of mature SARS-CoV-2); Cytokine storm, SARS-CoV-2 infection induces pro-inflammatory pathways (IL-6, TNF, CXCL 10, and cytokines) (Chen et al. 2021a, c). Blue, orange, yellow, and green boxes represent interventions of vaccines, drugs, antibodies, and traditional Chinese medicine plus and vitamins, respectively. CP, convalescent plasma

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Pharmacological intervention in COVID-19 therapy has investigated various possible candidates such as antiviral and anti-inflammatory drugs (Chen et al. 2021a; Ghareeb et al. 2021; Saleem et al. 2021). In pharmacological therapy, drug pharmacokinetic/pharmacodynamic issues are of great importance. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are apical membrane efflux transporters, are a crucial reason for these issues. These transporters are also one of the key factors in multidrug resistance (MDR) and affect the absorption, distribution, metabolism, and excretion of drugs in patients (Choi and Yu 2014). Many drugs have been identified as substrates and/or inhibitors of efflux transporters. Moreover, drug-drug interactions (DDIs), which lead to a reduction in a therapeutic effect or an increase in the adverse effect of a drug, should be considered in pharmacological therapy for patients with co-medications (Lazarou et al. 1998; Skvrce et al. 2011). In this review, we summarized therapeutic strategies for COVID-19 patients, especially those focused on pharmacotherapy and evaluated interactions of the current COVID-19 drugs with ATP-binding cassette (ABC) transporters P-gp and BCRP. We further examined the potential DDIs of COVID-19 drugs, especially those associated with P-gp and BCRP efflux transporters.

COVID-19

COVID-19 pathology

COVID-19 patients have various symptoms; fever, cough, labored breathing, muscle aches, dizziness, headache, sore throat, rhinorrhea, chest pain, diarrhea, abdominal pain, anorexia, nausea/vomiting, fever, and cough are the most common (Yan et al. 2020). Viral infection, morbidity, and mortality are influenced by intrinsic (sex, age, etc.) and extrinsic (lifestyle, underlying disease, etc.) factors. There are fewer SARS-CoV-2 infections among women than men (Conti and Younes 2020). ARD syndrome, an established COVID-19 pathology, is diagnosed at all ages, but the symptoms are more severe in adults than pediatric cases (Guan et al. 2020; Dudley and Lee 2020).

COVID-19 manifestations include not only pulmonary diseases such as pneumonia and ARD, but extrapulmonary indications including neurologic illnesses, ocular symptoms, thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, and dermatologic complications (Gupta et al. 2020; Moreira et al. 2021; Chen et al. 2021c; Mohamadi Yarijani and Najafi 2021).

Therapeutic strategies

Despite an incomplete understanding of the mechanisms of COVID-19 pathology, potential therapeutic strategies have been developed with various medical interventions (drugs, antibodies, vaccines, etc.) against fatal viral infection (Fig. 2).

Fig. 2
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Therapeutic strategies for COVID-19

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Pharmacological therapy (drugs)

Since the initial COVID-19 outbreak, drug repositioning to target SARS-CoV-2 has included many potential drugs that are antiviral, anti-inflammatory, or have other functions (Chen et al. 2021a, b; Ghareeb et al. 2021). These COVID-19 drugs target most steps of the viral infection cycle (host cell entry, replication of proteins and genomic RNA, and assembly [Fig. 1b]) and are used for the treatment of acute inflammation (cytokine storm) and various clinical symptoms. More details about COVID-19 drugs will be presented in the next section.

Immunological therapy (neutralizing antibodies and convalescent plasma [CP])

The generation of monoclonal antibodies against vulnerable sites on viral surface proteins provides a path to neutralize the COVID-19 virus. The SARS-CoV specific antibody CR3022 can bind to the SARS-CoV-2 S-gp receptor-binding domain (RBD) (Tian et al. 2020; Wang et al. 2020). Many other monoclonal antibodies are also used for intervention with COVID-19 infection, especially those targeting viral protein-host receptor interaction (Fig. 1b); 47D11, m396, CR3014, S230, S304, S309, and S315 (Zhang and Liu 2020; Yuan et al. 2020; Chen et al. 2021a). In addition, recombinant human ACE2-Fc fusion protein (rc-ACE2-Ig) can block viral entry into the host cell (Kruse 2020). The recombinant fusion protein provides a potential treatment avenue for COVID-19 infection with cross-reactivity and high binding affinity to RBD of SARS-CoV and SARS-CoV-3 (Lei et al. 2020).

Convalescent patient plasma containing antibodies (immunoglobulins G, A, M, E, and D) to SARS-CoV-2 can be used for hospitalized COVID-19 patients (Roback and Guarner 2020). CP therapy has been recommended by the United State Food and Drug Administration (US FDA) for the treatment of certain hospitalized COVID-19 patients (21 April 2021) issued as an Emergency Use Authorization (National Institution of Health 2021).

Vaccinal therapy (COVID-19 vaccines)

Vaccines, the most effective control for acquiring immunity and preventing massive outbreaks of infectious diseases, have been developed against SARS-CoV-2a using inactivated virus, mRNA, viral vector, and other forms: SinoVac (Corona Vac, inactivated virus, 50% efficacy, China), Pfizer-BioNTech (BNT162B1, mRNA, 95% efficacy, Germany), Moderna (mRNA1273, mRNA, 94% efficacy, USA), Janssen COVID-19 Vaccine (Ad26COVS1, viral vector, 73% efficacy, The Netherlands), AstraZeneca (ChAdOx1 nCoV-19, viral vector, 70% efficacy, England), Sputnik V (Gram Covid Vac, viral vector, 91% efficacy, Russia), Novavax (NVX-CoV2373, recombinant protein, 96% efficacy, USA), Sinopharm (BBIBP-CorV, inactivated virus, 79% efficacy, China), Covaxin (BBV152, inactivated virus, 81% efficacy, India) and CanSino (Ad5-nCoV, viral vector, 66% efficacy, China) (Saleem et al. 2021).

The mRNA vaccine system that translated the S-pg protein of SARS-CoV-2 after injection was first used in the COVID-19 pandemic (Pardi et al. 2018). Studies of the vaccines/vaccinations are continuing, and current COVID-19 vaccines such as those developed by Moderna, Pfizer-BioNTech, and AstraZeneca have shown poor safety data in aged and sensitive individuals (Soiza et al. 2021).

Other therapeutic approaches (medicinal plants and vitamins)

Many studies have provided evidence that medicinal plants and phytocomponents, consisting of traditional Chinese, Indian Ayurvedic, and homeopathic medicines are effective in the prophylaxis and treatment of COVID-19 (Reche et al. 2020; Tallei et al. 2020; Chu et al. 2021; Saleem et al. 2021). The natural compounds of flavonoids (quercetin, baicalin, luteolin, hesperidin, kaempferol, and curcumin), phenols (glycyrrhizic acid and lignan), quinones (emodin and skonin), alkaloids (matrine), and diterpenoids (andrographolide) have potent activity for inhibiting the viral infection cycle and for improving clinical symptoms (Fig. 1b) (Saleem et al. 2021). However, the therapeutic effects of Ayurvedic and homeopathic treatments were exhibited in asymptomatic COVID-19 patients rather than symptomatic patients (Reche et al. 2020).

Several studies suggested that vitamins, used for antioxidative and immune responses, can also target SARS-CoV-2 infection (Fig. 1b) (Ghareeb et al. 2021). Vitamin D reduces pro-inflammatory cytokines and increases anti-inflammatory cytokines, while its deficiency increases the severity of ARD (Grant et al. 2020). Vitamin C, vitamin B3, and vitamin B12 also help to improve the symptoms of COVID patients (Rosa and Santos 2020; Kandeel and Al-Nazawi 2020).

COVID-19 drugs

Due to the time-consuming nature of vaccine development, repurposed drugs have been a top priority for initial COVID-19 treatments (Table 1). Antiviral (affecting the steps of the viral infection cycle) and anti-inflammatory activities are major targets for COVID-19 drugs. Various therapeutic drugs, their classical uses, and their target sites and actions in SARS-CoV-2 infection are illustrated in Fig. 1b and Table 1.

Table 1 Current COVID-19 drugs; the candidate drugs and the approved drugs
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Antiviral drugs

Many potent COVID-19 drugs focus on antiviral activity.

Camostat, chloroquine, EK1C4, nafamostat, umifenovir, nelfinavir, quinacrine dihydrochloride and hydroxychloroquine prevent host cell entry of SARS-CoV-2 by blocking the interaction of the viral protein with the host cell receptor and blocking membrane fusion or endocytosis (Chen et al. 2021a, b; Ghareeb et al. 2021). Cyclosporin, disulfiram, favipiravir, lopinavir, remdesivir, ribavirin and ritonavir inhibit viral replication, including replication of viral protein and genomic RNA (Chen et al. 2021a, b; Ghareeb et al. 2021). Chloroquine and cyclosporin also target pro-inflammatory pathways induced by SARS-CoV-2 infection (Saleem et al. 2021; Chen et al. 2021a).

Chloroquine and hydroxychloroquine, classical antimalaria drugs, have potential actions for inhibition of virus post-translational modification (protein glycosylation), production of non-functional ACE2, as well as inhibition of viral cell entry (Oscanoa et al. 2020; Chen et al. 2021a). Moreover, they can be used not only as antivirals, but also as anti-inflammatories and anticoagulants (Oscanoa et al. 2020). These drugs are widely used for COVID-19 patients; however, their side effects include gastrointestinal (GI) disturbance, cardiac toxicity, hyperglycemia, and neuropsychiatric toxicity (Saleem et al. 2021).

Lopinavir and ritonavir, an amide analogue and a thiazole analogue, respectively, are protease inhibitors and antiviral drugs for the treatment and prevention of HIV/AIDS (Chen et al. 2021b; Ghareeb et al. 2021). These drugs are used in combination for HIV/AIDS treatment (Chandwani and Shuter 2008; Cattaneo et al. 2020; Biswas 2021). The combination drug has been broadly used for COVID-19 therapy but has induced multiple adverse effects such as GI disturbance, cardiac conduction abnormality, and hepatotoxicity (Ghareeb et al. 2021; Saleem et al. 2021).

Remdesivir, a broad-spectrum antiviral drug and an adenosine analogue, is used for COVID-19 therapy in adults and pediatric (> 12 years old and weighing > 40 kg) patients and has been approved by the US FDA (Saleem et al. 2021). The drug inhibits viral RNA replication (RNA polymerase function), but transaminase elevation and kidney damage have been reported as the adverse effects of this drug (Stebbing et al. 2020).

Among the above 15 drugs, chloroquine, cyclosporin A, disulfiram, hydroxychloroquine, lopinavir, nelfinavir, remdesivir, ribavirin and ritonavir have been approved by the US FDA for other uses, while camostat and nafamostat were designated orphan drugs by the US FDA (Table 1). Only remdesivir (Veklury) has been approved by US FDA for COVID-19 treatment (the first approved drug on 22 Oct. 2020), while ritovanir packaged with nirmatrevir (Palxlovid) has an emergency use authorization (EUA). With the exception of EK1C4, nelfinavir, and quinacrine dihydrochloride, the others are under the clinical trials (Table 1).

Anti-inflammatory drugs

Due to the acute inflammation (cytokine storm) generated by viral infection, anti-inflammatory drugs are also used for COVID-19 therapy. Baricitinib, dexamethasone, ruxolitinib and tocilizumab are used to inhibit pro-inflammatory pathways (Chen et al. 2021a; Ghareeb et al. 2021). Indomethacin and mycophenolic acid target SARS-CoV-2 replication and cell entry, respectively, and have potential anti-inflammatory effects as well (Chen et al. 2021a; Ghareeb et al. 2021).

Tocilizumab, a recombinant human monoclonal anti-interlukine-6 antibody, is used in COVID-19 patients (Luo et al. 2020). This antibody effectively inhibits cytokine storm and stabilizes the condition of severe or urgent patients (Ghareeb et al. 2021; Saleem et al. 2021). GI disturbance, skin/subcutaneous infections, and altered liver enzymes have been reported as adverse effects (Luo et al. 2020).

All the drugs mentioned above are US FDA-approved for other purposes, while baricitinb (Olumiant) has been approved specifically for COVID-19 treatment (10 May 2022) and tocilizumab has EUA (Table 1). Dexamethasone and ruxolitinib are under clinical trials (Table 1).

Anticancer drugs and antibiotics

Imatinib (an anticancer drug) and teicoplanin (an antibiotic) are also potent COVID-19 drugs. Both drugs are thought to inhibit COVID-19 infection by interfering with host cell entry of the virus in vitro (Chen et al. 2021a; Ghareeb et al. 2021).

Imatinib is a US FDA-approved drug and under the recruiting state for COVID-19 trials (Table 1). Teicoplanin (Targocid) was approved by the European Medicine Agency (30 Jul. 1988) and is available in many countries around the world (Vimberg 2021), but has not been approved by the US FDA.

Traditional Chinese medicines

Traditional Chinese medicines have been used for COVID-19 therapy from the early stage of the COVID-19 outbreak in China. COVID-19 medicines were developed based on the medicines used for the treatment of pandemic SARS, MERS and H1N1 influenza (Chu et al. 2021). Table 1 shows several Chinese medicines used to treat COVID-19 that were clinically trialed in China. These medicines are composed of various herb plants such as Isatis tinctoria L. (Banlagen), Lonicera japonica Thunb. (**yinhua), Paeonia lactiflora Pall. (Chishao), and Ephedia sinica Stapf (Ma huang); GI disturbance (nausea or diarrhea), abnormal liver function, heart palpitation and skin problems (itchiness or rash) have been reported as adverse effects (Chu et al. 2021).

Chinese medicines, which generally have few side effects, are being used clinically as well as in clinical trials in China (Table 1) (Chu et al. 2021).

P-gp and BCRP substrate and inhibitor drugs

ABC transporters, one of the largest transporter families, act as active efflux pumps related to pathogenic conditions as well as in normal physiological roles in living organisms (Trowitzsch and Tampe 2018; Liu 2019). P-gp (ABC subfamily B member 1 [ABCB1]; Fig. 3a) and BCRP (ABCG2; Fig. 3b), are widely expressed in important tissues such as the intestinal epithelium, the biliary canaliculi of hepatocytes, and the proximal tubules of the kidney, and are well-characterized MDR transporters among ABC transporters (Juliano and Ling 1976; Doyle et al. 1998; Robey et al. 2018; Dei et al. 2019). P-gp and BCRP are different in size and structure but are similar in their ATP-dependent function (dimerization) (Fig. 3c) (Robey et al. 2018; Dean et al. 2001). Numerous pharmacological agents are substrates and/or inhibitors of the transporters, and many drugs including antiviral and anticancer drugs are common substrates and/or inhibitors (Durmus et al. 2015; Chen et al. 2016). Efflux transporters affect drug pharmacokinetic parameters as well as MDR, and the US FDA has published guidelines for evaluation of transporter-mediated drug interactions (US FDA 2020).

Fig. 3
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ABC transporters. a P-gp consists of 12 transmembrane domains (TMDs) and 2 nucleotide-binding domains (NBDs) (approximately 150 kDa in size). b BCRP consists of 6 TMDs and 1 NBD as a monomer (approximately 72 kDa). c Drug efflux function of the transporters. ① A drug (substrate/inhibitor [green triangle] of the transporters) permeates into the cell membrane and binds to the affinity site in the TMD of the transporters. ② ATP binds to NBD and then it is hydrolyzed by ATP-hydrolyses. ③ The inward structure of the transporters changes to outward, and transporters efflux the drug to the extracellular region. The green arrows indicate the path of the drug

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It is important understand the association of current COVID-19 drugs, which are administered by an oral route (except remdesivir, nafamostat, teicoplanin and tocilizumab, which are administered via an intravenous route), with ABC transporters (P-gp and BCRP) located in the GI tract (Dei et al. 2019). We evaluated interactions of the COVID-19 drugs in Table 1 (except the traditional Chinese medicines) with P-gp and BCRP (Table 2). Thomas et al. predicted potential binding of repurposed COVID-19 drugs to P-gp via in silico studies, induced-fit docking and binding free energy calculation (Thomas et al. 2021). Remdesivir (− 2,687.21 (net binding energy)), baricitinib (− 2,471.25), indomethacin (− 2,441.04), arbidol (− 2,410.27), hydroxychloroquine (− 2,148.34), ritonavir (− 2,095.04), chloroquine (− 1,965.43), lopinavir (− 1,735.14), ruxolitinib (− 1,647.90) and favipiravir (− 636.90) can be substrates or inhibitor of P-gp (Thomas et al. 2021). According to a US FDA report, ‘Drug Development and Drug Interaction’, cyclosporin A and ritonavir are in vitro inhibitors for P-gp (26 Sep. 2016), lopinavir and ritonavir are clinical inhibitors for P-gp (26 Sep. 2016) and cyclosporin A is a clinical inhibitor for BCRP (26 Sep. 2016). Moreover, many in vitro studies (apical to basolateral penetration assay, substrate efflux/accumulation assays, and ATP hydrolysis assay) have demonstrated that potential COVID-19 drugs are substrates and/or inhibitors of P-gp and/or BCRP (Table 2) (Fricker et al. 1996; Tiberghien et al. 2000; Romiti et al. 2002; Vishuvardhan et al. 2003; Burger et al. 2004; Gupta et al. 2004; Houghton et al. 2004; Li et al. 2004; Sauna et al. 2004; Anglicheau et al. 2006; Elahian et al. 2010; Doshe et al. 2010; Rijpma et al. 2014; Elbert et al. 2016; Nayak et al. 2020; Buks et al. 2021; Telbisz et al. 2021; Weiss et al. 2021). Furthermore, in vivo studies (pharmacokinetic study, brain distribution study) also support that these drugs interact with P-gp and/or BCRP transporters as substrates and/or inhibitors of transporters (Table 2) (Schinkel et al. 1995; Kim et al. 1998; Breedveld et al. 2005; Huang et al. 2006; Wang et al. 2008). The oral bioavailability of nelfinavir (Kim et al. 1998) and quinacrine (Huang et al. 2006) increased approximately fivefold (a dose of 6 mg/kg) and 49-fold (multiple doses of 10 mg/kg/day for 7 days) in P-gp-knockout (Mdr1a−/−) mice (vs. wild-type mice), respectively. In the same animal model, brain penetration of cyclosporin A (Schinkel et al. 1995), nelfinavir (Kim et al. 1998), quinacrine (Huang et al. 2006) and dexamethasone (Schinkel et al. 1995) also increased 17-fold (a dose of 1 mg/kg), 36-fold (a dose of 3 mg/kg), 6–ninefold (a dose of 2 mg/kg) and 2.5-fold (a dose of 0.2 mg/kg), respectively, after intravenous injection. Mycophenolic acid levels in the plasma and brain after oral administration of mycophenolate mofetil (60 mg/kg), a prodrug of mycophenolic acid, were markedly increased in Mdr1a/1b−/− mice compared with wild-type mice (Wang et al. 2008). The area under the curve (AUC) of plasma imatinib after IV administration (12.5 mg/kg) was higher in Bcrp1 knockout mice and Mdr1a/1b knockout mice than in wild-type mice, and clearance of the drug significantly decreased 1.6-fold in Bcrp1 knockout mice and 1.25-fold in Mdr1a/1b knockout (vs. wild type), respectively. In addition, co-administration of pantoprazole (40 mg/kg) or elacridar (100 mg/kg), P-gp and BCRP inhibitors, significantly decreased imatinib clearance by 1.7-fold and 1.5-fold, respectively, in wild-type mice. Moreover, the brain penetration of imatinib following IV administration was also increased 2.5-fold in Bcrp1 knockout mice (vs. the wild type), and co-administration with inhibitors also significantly increased brain penetration of the drug (1.8-fold by pantoprazole and 4.2-fold by elacridar) (Breedveld et al. 2005). Table 3 presents pharmacokinetic information for COVID-19 drugs that possess potential or reported interactions with P-gp and BCRP transporters.

Table 2 The interactions of COVID-19 drugs with P-gp and BCRP transporters
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Table 3 Pharmacological or pharmacokinetic information of COVID-19 drugs related to the potential/reported interaction with P-gp and BCRP
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Most drugs (19 of 23) showed interactions or potential interactions with P-gp (predominantly) and BCRP as substrates and/or inhibitors (Table 2). Among the drugs interacting with these efflux transporters, chloroquine, cyclosporin A, lopinavir, nelfinavir, quinacrine dihydrochloride, remdesivir, ritonavir, baricitinib, dexamethasone, ruxolitinib, and imatinib (11 drugs) can bind to both P-gp and BCRP concomitantly. Remdesivir, baricitinib and ritonavir, which are US FDA-approved and FDA EUA drugs for COVID-19 treatment, require to pay a care this point when the drugs are used to treat the patients, especially, who take multiple medications. Indeed, the Liverpool Drug Interaction Group (COVID-19 Drug Interaction) recommended that ripamficin (an antibiotic), a well-known P-gp inducer, should not be co-administered with remdesivir because the strong induction of P-gp potentially reduces remdesivir level (Yang 2020). Other drugs under clinical trials (except nelfinavir and quinacrine dihydrochloride (preclinic)) also need to be considered in this light. These dual-interaction drugs control the host cell entry of SARS-CoV-2 (chloroquine, nelfinavir, quinacrine dihydrochloride, and imatinib), viral replication (cyclosporine, lopinavir, remdesivir, ritonavir and ivermectin), and acute inflammation (baricitinib, dexamethasone and ruxolitinib) in COVID-19. Camostat, EK1C4, nafamostat, ribavirin, and teicoplanin might not interact with efflux transporters. In vitro efflux assays showed that camostat was not an inhibitor of P-gp or BCRP (Weiss et al. 2021), and nafamostat was not a substrate of P-gp (Li et al. 2004) (Table 2).

In addition, P-gp polymorphisms have been associated with variability in the pharmacokinetics of lopinavir and ritonavir (Rakhmanina et al. 2011; Biswas 2021). The ABCB1 C3435T single nucleotide polymorphism (SNP), one of 50 SNPs in the ABCB1 gene and one that is highly prevalent in different ethnic groups [Europe (78%), America (67%), Asia (63.5%), Africa (41.4%)], might affect the pharmacodynamics and pharmacokinetics of lopinavir and ritonavir. High expression or low expression of this SNP can lead to therapeutic failure or adverse risk of the COVID-19 drugs (Biswas 2021).

Drug-drug interactions

DDIs are another important pharmacological issue. DDIs can decrease the therapeutic effect of drug and/or increase minor or serious unexpected adverse drug reactions (Lazarou et al. 1998; Skvrce et al. 2011). COVID-19 patients, especially those who are elderly or have co-morbidities such as cancer, cardiovascular, lung, and/or kidney diseases, take multiple drugs to remedy various COVID-19 symptoms and other diseases. Therefore, COVID-19 patients with polypharmacy need to be carefully monitored.

DDIs of COVID-19 drugs with other drugs used for managing other diseases have been reported (Cattaneo et al. 2020; Baburaj et al. 2021; Thomas et al. 2021). Lopinavir/ritonavir, chloroquine, hydroxychloroquine, and dexamethasone have potential DDIs with lung cancer medications. Among these COVID-19 drugs, lopinavir/ritonavir have potentially the most severe DDIs with many anticancer drugs (afatinib, brigatinib, cabozantinib, certinib, crizotinib, cyclophosphamide, dabrafenib, docetaxel, doxorubicin, entrectinib, erlotinib, everolimus, irinotecan, larotrectinib, lorlatinib, lurbinectedin, osimertinib, selpercatinib, topotecan, vandetanib, vemurafenib, vinblastine, and vincristine) and with antitubercular drugs (rifampin, clarithromycin, levofloxacin, moxifloxacin, ofloxacin, clofazimine, delamanid, and bedaquiline) (Baburaj et al. 2021; Thomas et al. 2021). Chloroquine, hydroxychloroquine, dexamethasone, and ruxolitinib were also identified to have potential DDIs with several antitubercular drugs (rifampin, clarithromycin, levofloxacin, moxifloxacin, ofloxacin, clofazimine, delamanid and bedaquiline) (Thomas et al. 2021). Ribavirin, remdesivir, and tocilizumab might not induce DDIs with lung cancer drugs (Baburaj et al. 2021), and remdesivir, baricitinib and tocilizumab might not be related to DDIs with antitubercular drugs (Thomas et al. 2021).

Hu et al. investigated the pharmacokinetic interactions between lopinavir/ritonavir and arbidol in an animal study. An oral co-administration of lopinavir (50 mg/kg)/ritonavir (12.5 mg/kg) and arbidol (25 mg/kg) significantly enhanced the AUC of arbidol (more than twofold) and the Cmax of lopinavir in rats (Hu et al. 2021). In northern Italy, the risk of potential DDIs was analyzed in hospitalized patients with COVID-19 (n = 502, mean age 61 ± 16 years (range 15–99 years) between 21 Feb. and 30 Apr. 2020) who had co-morbidities including cardiovascular, metabolic, lung, oncological, kidney, immune, and chronic infectious diseases (Cattaneo et al. 2020). Among the patients, 68% were exposed to at least one potential DDI, and 55% of patients were exposed to at least one potentially severe DDI. DDIs of co-medications, particularly with lopinavir/ritonavir, caused various and severe adverse events, and the combination of lopinavir/ritonavir and hydroxychloroquine induced a number of potentially severe DDIs resulting in a high risk of cardiotoxicity (Cattaneo et al. 2020). Remdesivir and tocilizumab were not observed to induce any potentially severe DDIs in hospitalized patients with COVID-19.

Remdesivir and tocilizumab could be safer with regard to pharmacodynamic DDIs when given with various drugs to treat co-morbidities than other COVID-19 drugs, whereas lopinavir, ritonavir, chloroquine, and hydroxychloroquine are assumed to lead to potentially severe pharmacodynamic DDIs (Cattaneo et al. 2020; Saleh et al. 2020; Baburaj et al. 2021; Biswas 2021; Thomas et al. 2021). COVID-19 drugs interacting with the P-gp and BCRP transporters (Table 2 and 3) also lead to pharmacokinetic DDIs. These pharmacokinetic DDIs, altering the absorption, distribution, metabolism, and excretion of medications, are more common than pharmacodynamic DDIs (Peng et al. 2021).

We examined the potentially severe efflux transporter-mediated DDIs between COVID-19 drugs by consulting the website of ‘Drugs.com (https://www.drugs.com/drug_interactions.html)’ and ‘COVID-19 Drug Interactions (http://www.covid19-druginteractions.org/checker)’, ‘drug prescribing information (downloaded from FDA website)’ as well as literature data. Major DDIs were monitored when the combination treatment of chloroquine-hydroxychloroquine, chloroquine-lopinavir, chloroquine-remdesivir, cyclosporin A-nelfinavir, cyclosporin A-ritonavir, cyclosporin A-baricitinib, disulfiram-ritonavir, hydroxychloroquine-lopinavir, hydroxychloroquine-remdesivir, lopinavir-nelfinavir, lopinavir-ritonavir, nelfinavir-ruxolotinib, ritonavir-ruxolitinib, baricitinib-dexamethasone, baricitinib-mycophenolic acid, baricitinib-ruxolitinib, baricitinib-tocilizumab, baricitinib-imatinib and ruxolotinib-tocilizumab were administered (Table 4). Combinations exhibiting major DDIs were not recommended. Although many other cases showed moderate DDIs, these combinations were also not recommended. On the other hand, the combination of cyclosporin A-lopinavir, lopinavir-imatinib, ritonavir-indomethacin and ruxolitinib-imatinib appeared to lead to only minor DDIs, which has minimal clinical significance and a low risk (Drugs.com/Drug Interactions Checker).

Table 4 Potential DDIs between COVID-19 drugs binding to P-gp and BCRP transporters
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In addition, the combination of favipiravir-chloroquine, favipiravir-cyclosporin A, favipiravir-hydroxychloroquine, favipiravir-lopinavir/ritonavir, favipiravir-remdesivir, favipiravir-dexamethasone, favipiravir-mycophenolic acid, favipiravir-ruxolitinib, favipiravir-tocilizumab, favipiravir-imatinib, remdesivir-lopinavir, remdesivir-baricitinib, remdesivir-dexamethasone, remdesivir-mycophenolic acid, remdesivir-ruxolitinib, baricitinib-lopinavir/ritonavir, baricitinib-mycophenolic acid, dexamethasone-mycophenolic acid, dexamethasone-ruxolitinib, dexamethasone-tocilizumab, ruxolitinib-mycophenolic acid, tocilizumab-lopinavir/ritonavir and tocilizumab-mycophenolic acid are not expected to lead to DDIs (COVID-19 Drug Interactions/Interaction Checkers and Drugs.com/Drug Interactions Checker). Drugs with minor or no DDIs can be considered in treatment with an adjusted regimen. Among the above DDIs, the combinations (bold and underline) of US FDA-approved and EUA drugs (remdesivir, baricitinib, ritonavir and tocilizumab) can be considered for the clinical trial. The possible or clinical mechanisms of DDIs between COVID-19 drugs are mentioned in Table 4. The mechanism of drug interaction has been mainly interpreted based on the activity of cytochrome P450 enzymes. However, the results from in silico, in vitro and non-clinical approaches to interactions with P-gp and BCRP provide the strong potential for the correlation of DDIs between COVID-19 drugs (Table 4, except tocilitinib) with these transporters (Schinkel et al. 1995; Fricker et al. 1996; Kim et al. 1998; Wang et al. 2008; Romiti et al. 2002; Vishuvardhan et al. 2003; Burger et al. 2004; Gupta et al. 2004; Houghton et al. 2004; Li et al. 2004; Sauna et al. 2004; Breedveld et al.2005; Huang et al. 2006; Anglicheau et al. 2006; Elahian et al. 2010; Doshe et al. 2010; Rijpma et al. 2014; Elbert et al. 2016; Tiberghien et al. 2000; Nayak et al. 2020; Buks et al. 2021; Telbisz et al. 2021; Weiss et al. 2021; Thomas et al. 2021). Overall, a better understanding of the pharmacokinetic and pharmacodynamic DDIs of COVID-19 drugs would be useful for managing pharmacological therapy in COVID-19 patients.

Conclusions

COVID-19, which is caused by SARS-CoV-2, results in ARD, fatal systemic manifestations (extrapulmonary as well as pulmonary), and premature mortality in patients. Clinical approaches to COVID-19 are the treatment of various symptoms and acute inflammation (cytokine storm) and the prevention of viral infection. Among various therapeutic strategies including immunological and vaccinal approaches, pharmacological therapy targets most steps of the SARS-CoV-2 infection cycle (cell entry, replication of proteins and genomic RNA) and inflammation (cytokine storm). Drug repositioning has been a priority due to the time-consuming nature of vaccine development for initial COVID-19 therapy.

We evaluated the interaction of current COVID-19 drugs with ABC transporters (P-gp and BCRP) and examined the potential DDIs of COVID-19 drugs, especially those associated with the efflux transporters. Most drugs interact with these transporters. Chloroquine, cyclosporin A, lopinavir, nelfinavir, quinacrine dihydrochloride, remdesivir, ritonavir, baricitinib, dexamethasone, ruxolitinib, and imatinib can bind to both efflux transporters, while EK1C4, ribavirin, tocilizumab and teicoplanin might not interact with any transporters. P-gp and BCRP-mediated COVID-19 drugs can lead to pharmacokinetic DDIs. Favipiravir may be safer than other COVID-19 drugs in terms of pharmacodynamic DDIs with various drugs to treat co-morbidities. Drug combinations of minor or no DDIs may be considered in clinical trials with an adjusted regimen. Moreover, combination therapy of remdesivir, baricitinib, ritonavir and tocilizumab (US FDA-approved and EUA drugs) with drugs which have little or no DDIs is expected to be widely used in the treatment of COVID-19, including favipiravir-remdesivir, favipiravir-tocilizumab, remdesivir-baricitinib, remdesivir-dexamethasone, remdesivir-mycophenolic acid, remdesivir-ruxolitinib, baricitinib-lopinavir/ritonavir, baricitinib-mycophenolic acid, dexamethasone-tocilizumab, tocilizumab-lopinavir/ritonavir and tocilizumab-mycophenolic acid. A better understanding of COVID-19 drugs and their potential pharmacokinetic and/or pharmacodynamic DDIs will be helpful in the management of pharmacological therapy for COVID-19.