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Bourdin, V.; Bigot, W.; Vanjak, A.; Burlacu, R.; Lopes, A.; Champion, K.; Depond, A.; Amador-Borrero, B.; Sene, D.; Comarmond, C.; et al. Drug–Drug Interactions Involving Dexamethasone in Clinical Practice. Encyclopedia. Available online: https://encyclopedia.pub/entry/52821 (accessed on 01 July 2024).
Bourdin V, Bigot W, Vanjak A, Burlacu R, Lopes A, Champion K, et al. Drug–Drug Interactions Involving Dexamethasone in Clinical Practice. Encyclopedia. Available at: https://encyclopedia.pub/entry/52821. Accessed July 01, 2024.
Bourdin, Venceslas, William Bigot, Anthony Vanjak, Ruxandra Burlacu, Amanda Lopes, Karine Champion, Audrey Depond, Blanca Amador-Borrero, Damien Sene, Chloe Comarmond, et al. "Drug–Drug Interactions Involving Dexamethasone in Clinical Practice" Encyclopedia, https://encyclopedia.pub/entry/52821 (accessed July 01, 2024).
Bourdin, V., Bigot, W., Vanjak, A., Burlacu, R., Lopes, A., Champion, K., Depond, A., Amador-Borrero, B., Sene, D., Comarmond, C., & Mouly, S. (2023, December 15). Drug–Drug Interactions Involving Dexamethasone in Clinical Practice. In Encyclopedia. https://encyclopedia.pub/entry/52821
Bourdin, Venceslas, et al. "Drug–Drug Interactions Involving Dexamethasone in Clinical Practice." Encyclopedia. Web. 15 December, 2023.
Drug–Drug Interactions Involving Dexamethasone in Clinical Practice
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12227120

Concomitant administration of multiple drugs frequently causes severe pharmacokinetic or pharmacodynamic drug–drug interactions (DDIs) resulting in the possibility of enhanced toxicity and/or treatment failure. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), a drug efflux pump sharing localization and substrate affinities with CYP3A4, is a critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs, including those involving dexamethasone. The recent increase in the use of high doses of dexamethasone during the COVID-19 pandemic have emphasized the need for better knowledge of the clinical significance of drug–drug interactions involving dexamethasone in the clinical setting. 

dexamethasone drug–drug interaction cytochrome P450 (CYP) 3A4 P-glycoprotein(P-gp) pharmacokinetics side effect

1. Introduction

Concomitant administration of multiple drugs frequently causes severe pharmacokinetic or pharmacodynamic drug–drug interactions (DDIs) resulting in the possibility of enhanced toxicity and/or therapy failure. A DDI occurs when the effects of one drug are changed by the presence of another drug, food or some environmental factor. Pharmacokinetic DDI may be divided into two categories, i.e., induction and inhibition of enzymes and transporters involved in drug metabolism and transport. The induction and inhibition of such enzymes and/or transporters may result in decreases or increases in the blood concentration of a drug, thus modifying the drug’s effects. Important advances in the knowledge of human drug-metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDI studies for use in drug development programs and in the clinical setting.
The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), a drug efflux pump sharing localization and substrate affinities with CYP3A4 is a critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs. Usually, the risk of significant DDI increases when a patient requires numerous medications, higher doses of medication and a longer duration of therapy, as observed in many patients who may be candidates to be treated with dexamethasone, classically described as a CYP3A4 and P-gp substrate and modulator [1].

2. Dexamethasone, an Increasingly Used Molecule

Apart from the use of -dose dexamethasone in endocrinologic diagnosis tests [2], this drug has mainly been used at high dosages in hematologic malignancy multi-drug protocols, especially in multiple myeloma [3], but also in lymphoma, most often as a second-line treatment; except in the management of mantle cell lymphoma, where dexamethasone is used as a first-line therapy [4]. Over the past 3 years, its utilization has, however, somewhat changed. The COVID-19 pandemic has dramatically increased the use of high-dose dexamethasone outside of the scope of hematologic malignancies, with proven efficacy in patients with severe COVID-19 infection [5][6][7]. Molecular analysis of its structure and binding affinities tends to confirm a specific activity on COVID-19 proteins, compared with other steroids [8]. In systemic autoimmune diseases, Prednisone remains the main used steroid, but high dosages of dexamethasone have recently been used in immune thrombocytopenic purpura, allowing a shorter course of therapy, and some authors recommend its utilization as a first-line treatment [9][10]. Consequently, the increase in dexamethasone prescription may be associated with increased frequency of DDI, as described in some observational database studies. In a large cross-sectional study of 444 elderly and diabetic Portuguese patients for instance, DDI between dexamethasone and fluoroquinolones, enhancing the risk of tendinopathy and tendon rupture, was found in 12 patients, and accounted for as much as 27% of potentially serious DDIs detected in this cohort [11]. A study of potential DDI with imatinib, performed in 544 French patients with at least one prescription of imatinib, a substrate and inhibitor of CYP3A4, revealed that dexamethasone, which was prescribed in as much as 23% of patients, was the third potentially interacting agent involved (after Paracetamol and proton pump inhibitors), leading to specific recommendations to prescribers [12]. This is consistent with a Chinese study on potential DDI with every oral antineoplastic agent (13.917 patients), which found interaction between these oral chemotherapies and dexamethasone in 117 patients (39% of every registered DDI in the study) [13].

3. Dexamethasone Pharmacokinetics, Metabolism, and Drug Interactions

The pharmacokinetics of dexamethasone in human subjects has been extensively studied and documented in the literature. As dexamethasone is almost eliminated from plasma within 24 h, single-dose studies are representative for a once-daily dosing regimen, which is the most common mode of administration in clinical practice. Overall, glucocorticoids display high oral bioavailability varying from 60% to 100% [14]. In humans, the fraction of administered dose systemically available for oral dexamethasone is 76% ± 10%. Dexamethasone is eliminated (Kel = 0.16) mainly by hepatic metabolism and renal excretions of the metabolites. Plasma concentrations follow a bi-exponential pattern [14]. Dexamethasone protein binding and hepatic metabolism have been well characterized in the literature. Key intrinsic (age, sex, body weight, ethnicity) and extrinsic (smoking) factors have been investigated.
The dexamethasone hepatic metabolism is a two-step process. Firstly, oxygen or hydrogen atoms are added then, secondly, conjugation takes place (glucuronidation or sulphation). Dexamethasone is extensively metabolized to 6-hydroxy-dexamethasone (6-OH-DEX) and side-chain cleaved metabolites in the human liver both in vitro and in vivo, with CYP3A4 responsible for the formation of 6-hydroxylated products [14]. Metabolites are excreted in the urine and the bile [15]. The renal excretion of unchanged dexamethasone is ≤10%. Dexamethasone is a well-known substrate [14] and inducer of CYP3A4 and P-gp and may therefore be subject to metabolic DDI, as noted in the CHMP “Note for Guidance on the Investigation of Drug Interactions” (CPMP/EWP/560/95). There is a reduced metabolic clearance rate (98 ± 43 l·m2 versus 153 ± 45 l·m2 daily) and prolonged plasma half-life (5.9 ± 2.2 h versus 3.5 ± 1.0 h) in patients with liver disease [16].

4. Clinical Rationale for the Study of Pharmacokinetic Drug–Drug Interactions Involving Dexamethasone

A dose–effect relationship for glucocorticoids was first described in 1967 in patients with multiple myeloma and intermittent high-dose dexamethasone was chosen for practical reasons. There is an excellent linear relationship between oral dexamethasone dose and, respectively, AUC and Cmax. However, AUC is independent of the individual oral solid dosage form and differences in bioavailability have a minor influence on AUC. No non-clinical or clinical studies have been conducted that specifically address the question whether the total exposure or the peak exposure to dexamethasone is more important for its pharmacodynamic action in these patients. There is evidence to suggest that total exposure is the relevant factor. In the first line treatment of multiple myeloma, dexamethasone is more effective when combined with other drugs than when administered alone, and that some drug combinations including dexamethasone are more effective than others. Furthermore, in the context of specific drug combinations, dexamethasone dosing may have prognostic implications. In COVID-19, a randomized controlled study comparing 6 versus 12 mg of dexamethasone failed to identify any statistically significant difference in terms of days alive without life support [17]. However, post hoc analysis highlighted interindividual variability and suggested that a dose of 12 mg could be more beneficial in some patients, yet the presence of co-medications (except for other immunosuppressive drugs) was not studied [18].

5. In Vitro Evidence of Drug–Drug Interactions Involving Dexamethasone

(A)
 Induction of CYPs by Dexamethasone: Role of Nuclear Receptors
(1) 
Induction of Liver CYP3A4
Members of the CYP3A subfamily, mainly the CYP3A4 isoform, are highly expressed in the human liver and small intestinal tract, playing a pivotal role in the systemic exposure of more than 50% of the currently marketed drugs [19]. CYP3A4 is the major drug-metabolizing enzyme in the human liver and small intestine and is responsible for the clearance of many commonly used drugs including steroids, benzodiazepines, statins, calcium channel blockers, direct oral anticoagulant medications and HIV-1 protease inhibitors. CYP3A4 has been shown to be inducible in humans by dexamethasone [20][21] Induction by a drug can affect not only the clearance of a concomitantly administered medication but also its own clearance (auto-induction) by the induced enzyme. Such induction is mediated by the binding of dexamethasone to nuclear receptors, mainly the Pregnane X receptor (PXR), the constitutive androstane receptor (CAR) and/or the Glucocorticoid receptor (GR) in a concentration-dependent manner [22]. Nuclear receptors are a class of proteins directly binding and interacting with DNA, regulating the expression of adjacent genes and acting as transcription factors. PXR and CAR are known to have an important place in the activation of several transporters and CYP family proteins.
  • (2) 
    Induction of Other CYPs
Dexamethasone also induced CYP2C9 expression and activity in human hepatocytes [23][24]. The CYP2C subfamily is an important class of drug-metabolizing enzymes responsible for the metabolism of up to 20% of all currently prescribed drugs [25]. In humans, this subfamily is composed of CYP2C8, CYP2C9, CYP2C18 and CYP2C19, with CYP2C8 and CYP2C9 being expressed at the highest level in the human liver [21]. In a study performed using primary human hepatocytes, 10 µM dexamethasone enhanced CYP2C8 mRNA two-fold, through GR activation, suggesting that dexamethasone might also induce CYP2C8 expression and activity in extra-hepatic tissues [25]. These results were consistent with studies performed in hepatocyte cultures and showing that dexamethasone increased human constitutive androstane receptor (CAR) by a GR-dependent mechanism and induction of CYP3A4, CYP2C8 but also CYP2B6 [26]. An enhancement of the effects of induction by known inducers such as phenobarbital and rifampicin has also been shown, with maximum induction of CYP2C8 and CYP2C9 at 0.1 µM dexamethasone, a dose at which neither CYP3A4 nor CYP2B6 were induced, suggesting complex mechanisms of regulation, involving all three nuclear receptors (PXR, CAR and GR) simultaneously [27]. CYP2A6 is expressed predominantly in the liver, representing between 1 and 10% of total hepatic P450s and responsible of the metabolism of substrates ranging from pharmaceuticals to toxins including procarcinogens, especially nicotine-to-cotinine C oxidation in smokers.
(B)
 Regulation of Expression and Activity of Transporters by Dexamethasone: Potential Implications for Drug–Drug Interactions
The modulation of expression and activity of drug-metabolizing enzymes and drug transporters by inducers is a major concern in the development of new drugs because it potentially leads to changes in the bioavailability of drugs and may disturb the balance between efficacy and toxicity [28]. Besides the liver, the small intestine expresses a broad spectrum of phase I and phase II drug metabolizing enzymes and transporters commonly referred to as phase III enzymes in drug metabolism. Phase I, II and III enzymes were shown to play a cooperative role in detoxifying and excreting xenobiotics, by liver and intestinal first-pass extraction.
  • (1)
     The Major Role Played by P-glycoprotein
P-glycoprotein (ABCB1, P-gp) is the product of the MDR1 gene in humans and was first characterized as the ATP-dependent transporter responsible for efflux of chemotherapeutic agents from resistant cancer cells. P-gp is located within the brush border on the apical (luminal) surface of mature enterocytes and on the apical surface of hepatocytes [29]. There is wide overlapping substrate specificity between CYP3A4 and P-gp, including drugs with a narrow therapeutic index, such as terfenadine, simvastatin, lovastatin, felodipine, amiodarone and midazolam [30] Although it has not been demonstrated so far, dexamethasone may induce their metabolism and transport, thus accelerating their elimination or preventing intestinal absorption, which in turn may decrease their efficacy.
  • (2) 
    Induction of P-glycoprotein by Dexamethasone
By using human jejunum originated from surgical resections and carefully prepared in a laboratory, Van de Kerkhof EG et al. showed that 100 µM of dexamethasone incubated for 24 h led to a four-fold induction of jejunal CYP3A4 mRNA, associated with a 50% increase in CYP3A4 activity, and a two-fold induction of jejunal MDR1 mRNA, the gene encoding for human P-gp [28]. Using sandwich-cultured rat hepatocytes and Rhodamine 123 as a model P-gp substrate, some authors observed that 10–50 µM of dexamethasone added to the hepatocytes for 48 h led to a significant three-fold increase in P-gp-mediated efflux transport of the model substrate and biliary clearance, but had a lesser effect on the biliary excretion index, suggesting increased hepatocyte uptake of Rhodamine 123 through induction of another transporter in rats [31]. As observed with CYP3A4, upregulation of P-gp expression and activity by dexamethasone was dose- and time-dependent, with maximal induction obtained with 10 µM concentrations, and strongly correlated with dose-dependent PXR upregulation [32].
  • (3) 
    Effect of Dexamethasone on Other Transporters and Metabolism Enzymes
Besides P-gp (the MDR1 gene product), other ABC transporters also catalyze the detoxification of xenobiotics and excretion of their conjugated metabolites in humans. In an in vitro study conducted on A549 cells (the non-small-cell lung cancer cell line) treated with dexamethasone, Pulaski L et al. showed a two-fold induction of the multidrug resistant protein MRP3 mRNA, while MRP2 expression was not induced [33]. In human embryonic kidney line-cells, dexamethasone increased MRP2- and MRP4-mediated transport of 3H-Methotrexate up to 170% and 140%, respectively [34]. These results highlight the fact that the scope of clinically significant DDI involving dexamethasone may go beyond CYP3A4 and P-gp. Breast cancer-related protein (BCRP), another ABC efflux transporter located all along the human small intestinal and canalicular biliary tracts, is responsible for the efflux of several widely prescribed medications such as methotrexate, mitoxantrone or non-steroidal anti-inflammatory drugs [35].
Organic anion transporting polypeptides (OATPs in humans, Oatps in rodents) belong to a growing superfamily of ATP-independent transport proteins that mediate uptake of structurally diverse amphiphilic organic solutes [36]. To the best of our knowledge, 11 human OATPs have been identified to date and some of them (namely OATP1B1 and OATP1B3) mediate the transport of a variety of drugs including rifampicin and dexamethasone. An induction of OATP1A4 by dexamethasone, via the difference between the level of biliary excretion index and the level of P-gp induction, has been hypothesized [31] but it has not been reported elsewhere.
(C) 
In Vitro Interaction between Dexamethasone and Other Treatments
In vitro experiments using mice and rat primary hepatocyte cultures and human liver microsomes showed consistently that docetaxel concentrations were significantly decreased by dexamethasone, which is associated with a 50% induction of P-gp efflux and/or CYP3A-mediated docetaxel metabolism [37][38][39]. In a work on a triple negative breast cancer cell line, the combination of docetaxel and dexamethasone did not decrease the cytotoxicity of docetaxel, which was even higher than with docetaxel alone, suggesting that, despite the DDI between either drug, efficacy may not be altered in the clinical setting [39]. Similarly, when dexamethasone and doxorubicin, both drugs being substrates of P-gp and CYP3A, were simultaneously administered, a significantly higher cell survival rate was observed as compared to the cell survival rate observed with doxorubicin alone [39].
(D) 
In Vitro Interaction with Dexamethasone as a CYP3A4 and P-gp Substrate
Besides its induction property, dexamethasone is also a substrate of CYP3A and P-gp. Therefore, DDI affecting the efficacy and toxicity of dexamethasone may occur. The level of its efflux by P-gp, estimated using transfected cell lines, showed an efflux-ratio of 3.7 compared to 1 without the presence of P-gp, consistent with the definition of a moderate substrate as compared to other corticosteroids [40]. However, cyclosporine A, at concentrations used in rheumatoid arthritis patients in clinical practice, may dose-dependently enhance the intracellular uptake of dexamethasone by inhibition of P-gp-mediated efflux, as shown in a human leukemic resistant cell line [41].
(E) 
In Vitro Studies General Conclusion
Collectively, these in vitro studies highlighted the role of dexamethasone in the regulation and modulation of the expression and activity of numerous transporters in human cancer cell lines and normal tissues. The activity of dexamethasone, as a substrate, may vary. Whether or not these findings may be extrapolated in vivo in humans is currently unknown and may be hard to conclusively determine given the species differences observed by some authors between rats and humans [42]. However, future studies will be warranted to confirm the major and growing role of uptake transporters in the drug–drug interactions that may occur with high-dose dexamethasone.

6. In Vivo Evidence of Drug–Drug Interactions Involving Dexamethasone

(A)
 Relative Contribution of CYP3A4 and P-gp in Drug–Drug Interactions Involving Dexamethasone in Animal Studies
The consequences of exposure to dexamethasone on the expression and function of liver and small intestinal CYP3A4 and on the expression and efflux of P-gp were previously evaluated in rats [43]. Compared to controls, CYP3A4 expression and activity (as measured by triazolam hydroxylation) in rat liver microsomes was increased by 10 to 14-fold by dexamethasone, with high correlation between CYP3A4 protein expression and activity. Intestinal P-gp protein expression was increased by 2.8-fold, while P-gp expressed in brain microvessels only increased 1.3-fold following dexamethasone treatment [43]. Changes observed in the expression and activity of liver and intestinal CYP3A4 and P-gp, at both mRNA and protein levels, were probably responsible for the cyclosporine-dexamethasone drug–drug interaction observed in rats treated with 1 or 75 mg/kg of dexamethasone once a day for 1–7 days. In this study, total cyclosporine clearance was unchanged but oral bioavailability was decreased by 30% after 7 days of treatment with 1 mg/kg dexamethasone. In rats treated with 75 mg/kg dexamethasone, the concentration of cyclosporine in the blood was significantly decreased after intravenous and oral administration, respectively. Cyclosporine bioavailability also decreased and total clearance significantly increased, consistent with a drug–drug interaction occurring at the liver and small intestine levels [44]. The respective role of P-gp and CYP3A in these mechanisms of absorption was studied in the intestine, with mdr1−/− knockout mice, without expression of P-gp. Expression of either gene’s mRNA was not homogenously distributed in the rat intestine, CYP 3a being more expressed in the upper intestine, than in the lower; MDR1 expression, being the exact opposite and that in physiological conditions; CYP3A expression in the upper intestine is the main determinant of cyclosporine absorption [45].
The role of P-gp has also been emphasized in a study on nadolol, a non-metabolized beta blocker, conducted in rats and showing that dexamethasone, given orally at 8 mg/kg/day for 4 days increased the P-gp levels two-fold in the liver and small intestine, which is consistent with previous findings, and decreased its systemic exposure by one-third, and increased its P gp-mediated renal excretion almost two-fold, which is consistent with a major role of P-gp in the DDI [46]. In rats pretreated with 100 mg/kg/day of dexamethasone given orally for two days, P-gp expression increased two-fold in the intestine, as previously observed, but not in the liver.
A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between dexamethasone and CYP3A and to resolve the drug- and system-specific PK/PD parameters for the course of induction [47]. A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of dexamethasone. The maximum induction of CYP3A mRNA via PXR transactivation by dexamethasone was achieved, showing a 21.3-fold increase relative to the basal level. The CYP3A protein was increased eight-fold and the total enzyme activity was increased almost three-fold, as previously described, with a lag-time of 40 h from the tmax of the dexamethasone plasma concentration [47]. These results were consistent with another work in which an oral and intravenous in vivo CYP3A probe (13C-erythromycin breath test) [48] was used with or without dexamethasone, in order to describe dexamethasone-mediated CYP3A induction in rats by means of a physiologically based pharmacokinetic model [49]. 
(B) 
Drug-Drug Interactions with Other Transporters in Animals
One study conducted in rats showed that dexamethasone reduced methotrexate biliary excretion by 53% and potentiated its hepatotoxicity in rats without affecting methotrexate pharmacokinetics and systemic exposure, presumably through the induction of uptake transporters located at the basolateral membrane of the hepatocytes (Oatp1a4 and Oat2), although upregulation of the efflux ABC transporter MRP2 and downregulation of MRP3, located in the canalicular (apical) membrane of the hepatocytes, were also observed in this study [50]. Whether these results should be extrapolated to humans deserves further confirmation. Inhibition of BCRP by dexamethasone in the placenta was also confirmed in a study on pregnant mouse placenta. A dose-dependent inhibition of BCRP at a high-dose of dexamethasone (1 mg/kg) with decreased mRNA levels and protein function, as attested by the accumulation of substrates in the fetus [51].
(C)
 Interaction by Unknown or Unspecified Mechanisms
In a mouse model of cysticidal infection, albendazole treatment efficacy (a CYP3A4 but not P-gp substrate) was significantly reduced by co-administration of dexamethasone at an inflammatory disease equivalence dosage, as attested by the number of alive parasites [52]. The exact mechanism of such DDI is unknown, as albendazole pharmacokinetics parameters are increased in the presence of concomitant dexamethasone treatment [53]. In an in vivo model of human ovarian carcinoma xenocraft on nude mice, a premedication with dexamethasone reduced the inhibitory effect of paclitaxel, another taxane family antitumor agent, on tumor growth by approximately 20% [54]. In a model of rheumatoid arthritis, a synergistic effect was observed between tofacitinib and dexamethasone, on paw growth with a 0.76 interaction factor [55]. Taken together, these studies indicate that dexamethasone-mediated induction of CYP3A-mediated metabolism and transport of widely used medications in various therapeutic areas may significantly influence clinical outcomes.

7. Drug–Drug Interactions Involving Dexamethasone in Humans

(A)
 Clinical Rationale
As mentioned above, members of the CYP3A subfamily of drug metabolizing enzymes are the most abundantly expressed cytochrome P450 enzymes in the human liver and small intestinal tract and are involved in the metabolism of more than 50% of clinically used medications. In addition, because many drugs, including some used in chemotherapy regimens, are metabolized in whole or in part by the CYP3A system, the determination of the role of dexamethasone in DDI observed in humans and the extent of CYP3A induction by dexamethasone in vitro and in vivo is important, because the relative role of well-described CYP3A inducers, such as rifampicin or carbamazepine, is well-described in the literature and they are known perpetrators of DDIs. Descriptions of clinically relevant DDIs involving dexamethasone is sparse and, as underlined by some authors, the majority of potential DDIs reported in databases are only theoretical [56].
(B)
 The Role of CYP3A Activity and P-gp in Drug–Drug Interactions Involving Dexamethasone in Humans: Published Evidence
As the influence of the CYP3A5 genetic polymorphisms on the extent of DDI involving CYP3A inducers is unknown, a clinical study was conducted in 27 healthy volunteers, half of whom were carrying the functional CYP3A5*1 allele and the half were not. The CYP3A activity was measured by means of the 14C-Erythromycin Breath Test, a specific and validated probe for liver CYP3A activity [48]. In this study, dexamethasone, 8 mg given orally twice daily, significantly increased the CYP3A activity by 50% in non-carriers of the CYP3A5*1 allele, while CYP3A was not significantly induced in those carrying the functional allele [57]. Hence, the risk of DDI involving dexamethasone in clinical practice may depend on the CYP3A5 genetic polymorphism that is not routinely determined except in some organ transplant recipients treated with tacrolimus, a well-known substrate of liver and small intestinal CYP3A4/5.
(C)
 Drug–Drug Interactions Involving Dexamethasone with Other CYPs in Humans
Dexamethasone may also interact with some other CYP substrates, such as CYP2C9, CYP2C8 or CYP2B6, which were shown to be inducible by dexamethasone. Voriconazole, a major antifungal agent approved in the treatment of invasive aspergillosis, is a substrate of multiple CYP450 isoenzymes mainly including CYP2C19, CYP2C9 and CYP3A4. Some case reports have reported treatment failure with voriconazole administered to cure invasive fungal infection, associated with suboptimal concentration of voriconazole due to coadministration with dexamethasone, consistent with a previous pharmacokinetic study showing that dexamethasone decreased voriconazole trough concentrations at suboptimal therapeutic levels [58][59][60].
(D)
 Dexamethasone Pharmacokinetics May Also Be Affected by Well-Known and Potent CYP3A/P-gp Modulators in Humans
The pharmacokinetics of dexamethasone may also be affected by CYP3A4 and/or P-gp modulators, some of which are widely prescribed by physicians in various therapeutic areas in clinical practice. A randomized crossover study versus placebo conducted in healthy volunteers receiving 4.5 mg oral or 5 mg intravenous dexamethasone revealed that the potent CYP3A4/P-gp inhibitor itraconazole markedly increased dexamethasone plasma concentrations and enhanced its adrenal-suppressant effect when given at 200 mg/day [61]. The systemic exposure of oral and intravenous dexamethasone was increased 3.5-fold, together with a three-fold increase in the elimination half-life. Intestinal absorption of oral dexamethasone was also 50% faster with itraconazole, as ascribed by the 50% decreased Tmax, consistent with possible inhibition of intestinal P-gp-mediated efflux of the steroid [61].
(E)
 Impact of Pharmacogenomics on the Potentiality and Prediction of Dexamethasone Induced DDIs
As previously published [57][60], genetic background can significantly influence the occurrence and clinical relevance of DDI. A growing number of single nucleotide polymorphisms (SNPs) have been identified and are currently studied to predict inter-individual variability of drug efficacy and toxicity. However, despite evidence of the role of genetic background in the occurrence of DDI’s, even suggesting drug-drug-gene interactions [62], only a few pharmacogenomic-based studies have proved to be useful in individualizing drug treatment and dosing regimen, e.g., anti-platelet agents or anti-depressant drugs [63][64], or reducing the incidence of clinically relevant adverse drug reactions [65]. A modern approach with bioinformatics tools, combining a larger panel of genes and a faster computerized approach, may help the clinician to reduce the risk of DDI, although generalization and the feasibility of such an approach has yet to be determined [66][67]. Regarding dexamethasone, the genes encoding for transport proteins and metabolizing enzymes involved in its liver first-pass and pre-systemic metabolism are commonly studied.

8. Overall Conclusions

Dexamethasone has well-established clinical indications, involving both systemic and local administration, regarding its anti-inflammatory, immunosuppressant and antineoplastic properties. There is strong in vitro and in vivo evidence that dexamethasone, at a clinically relevant dosing regimen, e.g., doses used in the treatment of COVID-19 infection or hematologic malignancies, is a potent inducer of CYP3A4, CYP2C9, P-gp, and presumably other transporters, as confirmed in several studies including human studies or case reports. Despite the lack of warnings regarding the clinical relevance of such DDIs in daily practice, prescribers should be aware that dexamethasone, especially at the high dosages used clinically, may significantly alter the efficacy and safety of drugs with a narrow therapeutic index, such as substrates of CYP3A4 and P-gp, as has recently been observed in COVID-19 patients treated with the antiviral nirmatrelvir and concomitantly receiving potent CYP3A4/P-gp inducers [68]. Moreover, as dexamethasone is a substrate of CYP3A4, it may also be susceptible to DDI when administered with strong inducers or inhibitors such as rifampicin, phenytoin or carbamazepine [69][70]. Better knowledge of an individual patient’s pharmacogenetic background and a pharmacogenomic-based approach may be useful in anticipating DDI between individual drugs in the clinical setting. The recent substantial increase in the use of dexamethasone in clinical practice during the COVID-19 pandemic has highlighted the urgent need of clinical DDI studies to optimize dosing regimens in patients with comorbidities and concomitant medications.

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Venceslas Bourdin
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