Cytochrome P450 enzymes (CYPs) are polymorphic proteins bound to a cell and heme component which absorb at the 450 nm wavelengths when exposed to carbon monoxide. They are essential to the biosynthesis of steroids, prostacyclin, and thromboxane A2 (19). CYP enzymes are ubiquitous, however they are mainly expressed in the liver, and small intestine forming CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 as the predominant forms, which are responsible for metabolizing 90% of drugs (18, 19). Of the different CYP enzymes identified and studied, CYP3A4 and CYP2D6 are considered the most important drug-metabolizing enzymes due to their abundance in the small intestine and the liver as well as their ability to metabolize a plethora of xenobiotic substances (20, 21). Variation in response to therapy can, at least in part, be attributed to differences in the activity and/or the extent of these enzymes (20–22). Drugs and non-drug factors may interact with these enzymes, acting as substrates or leading to induction or inhibition, thus affecting the action and disposition of drugs.

Inflammation is also associated with altered transporter gene expression in addition to CYP expression (Figure 3) (74). Drug transporters play a vital role in the absorption, distribution, and elimination of medications. Transporters are a part of two superfamilies; solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters, found across various tissues which coordinate and regulate the flow of molecules across membranes (75). In terms of function, the SLC transporters typically are involved in the influx of molecules into cells and tissue, whereas ABC transporters are commonly efflux transporters, with both families containing multiple subtypes. During inflammation, evidence suggests these transporters are downregulated in the liver and kidney, specifically, there is downregulation of influx transporter genes organic cation transporter (OCT)-1, organic anion-transporting polypeptide (OATP)4A as well as efflux transporter gene, MRP1, in the liver. This suggests a change in extraction and intrinsic clearance of the drug as less is passing through the liver. The change in extraction ratio was seen experimentally with propranolol and verapamil, changing from high and intermediate to low extraction drugs, respectively (35, 39). Additionally, cellular models have shown that transporters such MRP2 in the jejunum were also downregulated in general inflammation, with other transporters exhibiting time-dependent suppression, such as ABCB1 which is only downregulated for the first 48 h (76).

In chronic inflammatory conditions such as RA, human cell studies have observed downregulation of transporters such as OAT1B1, with a marked reduction in ABCC2 by 50%, and SLC10A1 by 75% compared to control as a result of IL-6, which is typically elevated in RA (77, 78). This in turn results in lower uptake of medications like fluvastatin for hepatic clearance, leading to a total decrease in clearance of the drug by 40%–50% in RA patients (77). However, the plasma concentrations of CRP or cytokines does not correlate with the pharmacokinetic parameters of fluvastatin when the analysis was performed. Further, there is no significant differences in the unbound fraction that is mentioned. In other inflammatory conditions such as ulcerative colitis (UC) human biopsy studies have found that there was a significant 3-fold reduction in ABCB1 efflux transporters, along with a 6-fold decrease of ABCG2 (76). These transporters are regularly involved in the efflux of UC medications, and due to their downregulation, there is elevated concentrations of drugs used in UC such as steroids, 5-aminosalicylate, and cyclosporine A. This sentiment has been echoed in other animal-based studies where other efflux transporters found in the liver and intestines, such as P-gp, were downregulated by approximately 50% in UC (79). As a result of the downregulation, when the UC rats were administered cyclosporine A, there was an approximately 1.78-fold increase in plasma drug concentration compared to control.

Furthermore, exposure to 100 ng/mL TNF-α or 10 ng/mL IL-6 for 48 h was found to down-regulate mRNA levels of major sinusoidal influx transporters, including sodium-taurocholate cotransporting polypeptide, OATP1B1, OATP1B3, OATP2B1, OCT-1, and organic anion transporter 2 (80).

Despite much work done on the effect of various factors on the CYPs formation and clearance, drug-receptor target proteins have been largely ignored in this context.

There is no reason for proteins other than CYPs to remain unaffected by inflammation. Indeed, down-regulations of various cardiovascular target proteins have been reported (Table 2). Such down regulations are bound to have clinical consequences with respect to pharmacotherapy. For example, the cardiovascular effect of verapamil is shown to be reduced in humans with active arthritis (38), obesity (81) and in old age (82). Surprisingly, in all these studies the reduced effect of verapamil has been observed despite the elevated drug concentration. The increased drug concentration is expected due to the down regulation of CYPs needed to clear the drug as well as increased drug plasma protein binding. Later data generated from experimental animals demonstrated that these lower than expected effects were due to downregulation of calcium channel target proteins that are essential for the effectiveness of verapamil (36). These observations suggest that inflammation down regulates both of the involved proteins, the one responsible for its clearance, as well as the one needed for the drug-receptor interaction.

The receptor downregulation is also observed for propranolol administered to rats with adjuvant arthritis (32). Furthermore, sotalol, which has low plasma protein binding and is renally eliminated, also demonstrated a reduced PR interval in AA rats compared to control, suggestive of downregulation of the drug’s target receptor in the absence of protein binding involvement (85). This effect on the pharmacodynamics, however, was reversed when inflammation was controlled with the administration of infliximab (35). Verapamil’s reduced effect in extending PR intervals in AA rats was also reversed when combined with valsartan, an antagonist to the proinflammatory mediator; angiotensin 2 (83).

For the downregulation of β1-adrenergic receptors cause by inflammation (32), a link with norepinephrine transporters is suggested (89). Hyperactivity of sympathetic nervous system has been shown in rheumatoid arthritis with a potential link to the cardiovascular mortality (90–92). In addition, the norepinephrine transporter functionality has a strong role in dictating the distribution of sympathetic innervation (93).

It has been shown that, in experimental inflammation, not only are the cardiac β1-adrenergic receptors target proteins down-regulated, but the norepinephrine transporters are also reduced (Figure 4) (89). Such a down regulation in the neurotransmitter receptor is proposed to cause a reduced uptake of norepinephrine by the nervous system.

Given that a significant proportion of patients with RA also experience cardiovascular diseases (94, 100, 102), more attention should be paid to the effect of inflammation on the pharmacokinetics and pharmacodynamics of drugs to avoid treatment failure and poor prognosis. Patients suffering from active RA have been found to exhibit altered pharmacokinetics of different cardiovascular medications. It has been reported, as compared with healthy subjects, they have higher concentrations of verapamil due to decreased clearance, but interestingly, show reduced dromotropic effect which is suggested to be due to down-regulation of the target receptor proteins (37) (Figure 5).

These effects are normalized when the disease and/or inflammation is brought under control due to remission and/or pharmacological intervention. Ling et al. have found no significant difference in PR prolongation in response to verapamil between healthy subjects and patients who have their RA controlled by using infliximab or conventional anti-inflammatory drugs (84). A PR interval prolongation indicate blockade of the calcium channels. Data generated from experimental arthritis confirm normalization of CYP1A and CYP3A isoenzymes down regulation by infliximab (35).

Experimental animal studies have demonstrated that the inflammation-induced down regulation of calcium channels receptors is reversed by angiotensin II receptor antagonist valsartan [Figure 6, (83)], likely through the drug’s direct free radical scavenging and indirect anti-inflammatory actions by inhibition of the pro-inflammatory mediator angiotensin II (109). This observation is in line with the clinical practice of combination therapy (110).

Fluvastatin is an HMG-CoA reductase inhibitor (statin), which exhibits higher plasma concentrations in RA than in healthy subjects. This has been shown to be due to inhibition of OATP1B1 transporter which is inhibited by the disease (77). Furthermore, higher exposure for another statin, simvastatin, in RA is attributed to inhibition of its metabolism that appear to normalize by the anti-inflammatory sarilumab (78). Whether the increased statins concentration in RA causes increases in the incidence of myalgias remains to be seen.

It is well acknowledged that a major contributor to the CYP suppression in RA is linked to the elevated levels of IL-6. This is also further supported by the administration of biologics designed to target IL-6 or IL-6 receptors, such as tocilizumab, ruxolitinib, or sarilumab, resulting in restored CYP function along with lower drug plasma concentrations compared to untreated RA patients (101–106).

Data generated using experimental arthritis suggest that the disease affect β1 antagonists such as propranolol in a fashion similar to the verapamil observation, i.e., increased concentration but reduced effect (Table 2).

It is important to note that the effect of angiotensin interrupting drugs such as losartan (107) and valsartan (108) is not altered by arthritis suggestive of lack of influence of the disease (i.e., inflammation) on the related receptor (Table 2). Another equally interesting finding is regarding nebivolol, a third generation β-adrenoceptor blocker with high selectivity for blocking β1 and β3-agonistic properties. In experimental arthritis, neither action nor disposition of nebivolol is reported to be influenced by inflammation despite the reduced β1-AR expression, but no change in that of β2 and β3-AR (86). This is suggestive of the predominance of contribution of β2 and β3-AR to the action of nebivolol on blood pressure. In addition, the lack of an inhibitory effect of inflammation on the clearance of nebivolol is suggestive of mechanisms other than an efficient hepatic metabolism for its low bioavailability. Thus, like the AT1 antagonist, e.g., losartan and valsartan, a β2 and β3-AR blocker is a suitable choice to control blood pressure in the presence of inflammatory condition.

RA patients experience cardiovascular complications substantially higher than the general population (94), and the receptor proteins alteration is only a part of the effect of inflammation on the cardiovascular system. For example, inflammation is reported to influence two other important pathways involved in regulating cardiovascular function, namely the arachidonic acid metabolism and the renin angiotensin system (RAS). Inflammation brought about by adjuvant arthritis is shown to cause tissue-dependent imbalances of arachidonic acid metabolites. It elevates the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids in the heart but reduces the ratio in the kidney (95).

The hormonal system RAS controls cardiovascular function by maintaining balances in body fluid volume, blood pressure in both health and disease (96). Inflammation causes imbalances in the gene expression of angiotensin converting enzymes toward cardiotoxicity (97) (Figure 7). In addition, the peptides involved in the RAS are also affected. The cardiac and renal biologically active peptides (Ang II and Ang1-7) and the target proteins involved in the peptide-receptor binding (Ang II type 1 and type 2, and Ang1-7 receptor, Mas) are altered toward cardio-renal toxicity (98).

Crohn’s disease is an inflammatory bowel condition which involves an intestinal insult that disrupts barrier function in the gastrointestinal tract, thus affecting absorption and potentially drug metabolism (37). It is associated with many cardiovascular manifestations, such as heart failure, pericarditis, thromboembolism, which are typically treated with CYP substrates (113). Given that the intestine is involved in first pass metabolism, and highly concentrated with CYP3A4, the effect of hyperinflammation may influence the treatment efficacy (111). In one study, the authors found reduced CYP3A4 content in the intestinal biopsies from patients with active Crohn’s disease (112). Ulcerative colitis (UC) is a condition similar to Crohn’s disease but is usually restricted to the large intestine. Its symptoms include erosion and ulcers in the intestinal mucosa (76). The chronic inflammatory state in the gastrointestinal tract of animal and UC patient causes a significant reduction in CYP3A, CYP2C9, UGT1A, and drug transporters genes such as ABCBG2, ABCB1, and SLC16A1 which downregulate transporters such as P-GP (76,112–114). These enzymes are important for the bioavailability of UC medications, as many of them are substrates for those transporters, and could be attributed to the altered drug concentrations in UC patients. The therapeutic consequences of these finding remain to be studied.

Another report reveals that Crohn’s disease caused elevation of verapamil concentration in plasma. However, indeed, the efficacy of verapamil to prolong PR interval was very much dependent on the disease severity, the higher the severity the less the efficacy (Figure 8) (37). This observation is in line with what has been reported for other inflammatory conditions, e.g., RA. Once the disease (i.e., inflammation) is controlled, the downregulating effect on the calcium channels is reduced.

Cancer, is also associated with inflammation as tumor cells release cytokines and chemokines which recruit leukocytes and other proinflammatory mediators (115). Also, CYP enzymes are involved in both the pathogenesis and treatment of cancer, as they metabolize carcinogens as well as activate anticancer drugs.

The effect of inflammation on the pharmacokinetics of anticancer drugs is relevant when considering treatment options for cancer patients as many antineoplastic agents have a narrow therapeutic window and are either metabolized or activated by CYPs. For instance, the chemotherapy agent docetaxel is predominantly cleared by CYP3A4. Severe toxicity has been shown to be 3-fold higher for patients with elevated inflammatory markers (AAG and CRP) (116). It is postulated that the higher the levels of AAG, the greater the inflammatory response and thus, the more suppression of CYP metabolism hence greater toxicity (117). The suppression of CYP3A4, has been observed in the presence of specific elevated cytokines such as IL-6, TNF-α and CRP (118). Mediators such as IL-6 and TNF-α can act as biomarkers for impaired clearance as elevated in cancer patients (119). Mimura et al. have reported that the treatment of three-dimensionally cultured functional liver cell line with IL-1b or IL-6 caused a concentration-dependent decrease in CYP3A4 protein expression and its catalytic activity (72). TNF-α treatment had no effect on CYP3A4 protein expression or its catalytic activity (as measured by formation of triazolam metabolite, hydroxy-triazolam) although it did decrease mRNA. The cell model illustrated modulation of CYP3A4 expression by cytokines, increased toxicity of chemotherapy agents by IL-6, and restoration of CYP3A4 mRNA expression by anti-cytokine agents (72).

It appears that malignant tissues have increased expression of CYP enzymes such as CYP2E1 and CYP3A4 (120–123). Cancers such as those of advanced ovarian breast and coflorectal cancers are associated with upregulation of certain CYP enzymes. CYP2E1 activity measured by 6-hydroxychlorzoxazone/chlorzoxazone ratio has been reported to be markedly up-regulated in cancer (1.30 vs. 2.75). This is while CYP3A phenotypic activity measured by omeprazole sulfone/omeprazole ratio is shown to be reduced in cancer (0.23 vs. 0.49) (122).

The therapeutic outcome of these changes in CYPs, and other important target proteins is mainly unknown although their possible involvement in the variation in response cannot be ruled out. Moreover, more recently, targeted immunomodulators that are being used to make treatment more precise, enhance cytokine release (131), thus potentially influencing efficacy of other drugs.

Obesity is an independent risk factor for many diseases, including hypertension, diabetes, arteriosclerosis, arthritis, among others. Adipose is an active endocrine and paracrine tissue which releases adipokines, pro-inflammatory cytokines as well as NO (124). Increased plasma CRP concentrations and elevated inflammatory markers have been illustrated in obese patients, resulting in CYP downregulation (125). In addition to the changes in metabolizing enzymes, obesity is often associated with hyperlipidemia, leading to a higher concentration of lipoproteins. Given that many drugs have a high binding capacity to lipoproteins, an excess of it may be associated with a higher total drug concentration. However, there is a paucity of studies looking at lipophilic drugs to assess this possibility. In addition, a very few studies have focused on the therapeutic relevance of these obesity-driven changes (81, 130).

Rise and fall in TNF-α and IL-6 have been found to be correlated with weight loss, respectively (126). Both these cytokines are linked to insulin resistance, endothelial dysfunction, and cardiovascular disease, thus involved in the pathophysiology of diabetes and hypertension (124). Animal studies have shown an isozyme specific effect on CYP enzymes with obesity, with a decrease in CYP3A, and increase in CYP2E (127–129). Additionally, some mouse studies have also illustrated a downregulation of CYP1A1, and steroidogenic acute regulatory protein in obese mice, resulting in altered steroid metabolism and deficiency in the mouse’s sperm (127).

Rat models on a high fat diet have shown reduced concentrations of a lidocaine metabolite consequent to reduced expression of CYP3A1, CYP1A2, CYP2C12 (131). Moreover, rats on high fat diets for 40 weeks showed a 43% decrease in CYP enzyme expression (130). A study on obese human subjects, on the other hand, attributes the changes in the pharmacokinetics of lidocaine to increased volume of distribution consequence of increased body volume in obesity (131).

Evidence for altered pharmacokinetics of drugs in obesity of humans and experimental animals is abundant (e.g., ibuprofen, salicylates, brexiprazole, morphine, amoxicillin, fluconazole, triazolam) (125). Unfortunately, however, due to the lack of corresponding pharmacodynamic data, the clinical outcomes of these finding have remained mainly unclear. A mere altered pharmacokinetic profile does not necessarily mean altered clinical outcome.

For example, in obsess adults (81) Abernethy et al reported a substantial increase in the plasma concentration of verapamil with a three-fold prolongation of terminal half-life but no increase in measured effects. Indeed, there was an increased EC50 in obese patients to prolong P-R interval as compared with controls (45.9 ± 6.7 vs. 22.6 ± 2.0 ng/mL; p < 0.005). The authors speculated a “decreased direct verapamil effect and/or impaired baroreflex sensitivity, sympathetic, and parasympathetic reflex responses due to verapamil-induced hypotension in obese as compared to normal-weight hypertensive patients” for their observation (81). However, a down-regulation of the calcium channel receptor target protein, as has been shown in other inflammatory conditions, is likely responsible for this observation.

The above findings are in concert with another set of data generated bu studying obese children. The study has illustrated a significant reduction in the efficacy of calcium channel blockers used to control blood pressure (132). The study’s goal was to demonstrate a 10% reduction from the baseline systolic BP after administering calcium channel blockers. The number of patients that achieved this outcome was significantly lower in the obese patients (12.5%) than in the non-obese group (52.9%) (132) (Figure 9). Drug exposure had not been measured in these patients, but it is reasonable to assume that it has not been reduced, but likely increased in this population. Thus, the reduced effect in these patients is unlikely to be due to reduced concentration.

HIV is characterized as an inflammatory disease due to the presence of elevated cytokines, commonly IL-6, and the increased activity of T lymphocytes continuously combating the virus (133). Many drug regimens rely on the inhibition of CYP enzymes with protease inhibitors such as ritonavir, to maximize pharmacological drug cocktail efficacy. A small human study has shown that, compared with healthy controls, ten HIV-infected men and women had 18% lower hepatic CYP3A activity and 90% lower CYP2D6 activity (134). Additionally, another study has noted that the more poorly controlled HIV, the higher would be the cytokine levels (135). Moreover, one study looked at inflammation-mediated modulation in apparent clearance of atazanavir (136). An inverse correlation has been observed between rising bilirubin secondary to the inhibition of UDP glucuronosyltransferase mediated by atazanavir, and CRP, IL-6, as well as TNF-α- indicating an anti-inflammatory effect mediated by drug therapy. Although these studies provide an introductory insight on CYP modulation in HIV, the results are confounded by the anti-inflammatory effects of the pharmacological therapy thus, more research is needed to understand the impact of the cytokines, and the effect on the antiretroviral pharmacokinetics and therapy outcomes.

During infections with influenza, and COVID-19, the body employs the innate and adaptive immune system to combat the virus. This, in turn, results in the rise of inflammatory cytokines and the establishment of a systemic inflammatory response. Indeed, anti-inflammatory therapy is an essential part of treatment of infected patients (137, 138). The associated inflammation impacts the metabolism of certain medications such as theophylline used in asthmatic kids when infected with influenza B. Children with a CRP above >0.5 mg/d developed an increase in theophylline toxicity, along with a decline in theophylline clearance, attributed to a downregulation of CYP1A2 (139, 140).

COVID-19 is associated with complications such as thromboembolic events, superimposing bacterial infections, and respiratory distress that contribute to poor outcomes if not promptly treated with properly dosed antithrombotics and antimicrobials, respectively (141–144). With the novelty and spectrum of severity of COVID-19, and the prominence of inflammation associated with disease progression, the effect on action and disposition of medications should be considered, especially in older adults with multiple comorbidities already on a cocktail of medications, as they are the most affected group (145). During the incubation period of the virus, the immune system generates a multitude of cytokines to eliminate the virus and prevent it from reaching a severe state. In certain individuals, the immune response is weak, allowing viral replication to progress. This failure leads to the recruitment of adaptive immune cells to mitigate the viral load (146). If the dual action of innate and adaptive immune responses fails, a cycle of cytokine recruitment is initiated, leading to a pathogenic positive feedback loop called cytokine storm syndrome (147, 148). This results in hyper-inflammation and damage to tissues as well as a possible alteration in drug response as an influx of cytokines that are known to affect pharmacokinetics of drugs are now substantially increased in tissues involved in metabolism of xenobiotics. Additionally, recent studies propose that the virus binds to ACE2 in the alveoli, a receptor that regulates the conversion of angiotensin 2 (a pro-inflammatory mediator) into its anti-inflammatory metabolite, angiotensin 1-7. This occupation of ACE2 results in its depletion in the lungs, causing an imbalance in the inflammatory mediators (elevated angiotensin 2) - leading to greater inflammation in the area, and pulmonary distress (149). Losartan, an ACE2 receptor blocker, affected the SARS-CoV-2 replication of Vero E6 cells in vitro (154).

Aside from respiratory distress, extrapulmonary effects such as hepatic manifestations have been reported (146, 149). The infection is accounted as being like a sepsis-like inflammation due to its ability to manifest cytokine storms because of the immune system’s hyperactivity. This feedback loop illustrates the effects cytokines can impose on CYP metabolism, alteration in target receptors, and changes in drug transporters. Cytokines and other inflammatory mediators can have critical implications on the metabolism of drugs used for symptom control. The currently approved drugs for the treatment of COVID-19 are substrates for CYP2C8, CYP2D6, and CYP3A4 enzymes, as well as OATP1B1, and P-glycoprotein drug transporters (P-gp) (150). Remdesivir is also a weak inhibitor of CYP3A4, OATP1B1, and OATP1B3. Based on previous data on the effects of inflammation on these proteins, the impacted metabolism, and the affected efficacy of the drug could have significant consequences in terms of drug related toxicity, subtherapeutic activity of the drug, and impaired clearance within the patient.

Inflammation’s impact on COVID-19 therapy has been observed in some recent studies involving the use of the HIV drug lopinavir/ritonavir used to treat COVID-19. These studies have found that the concentration of lopinavir in COVID-19 patients has been 3.5-fold higher than HIV patients (102). In COVID patients, a significant positive correlation is found between lopinavir plasma concentrations and CRP values (r = 0.37, p < 0.001). The measured lopinavir concentration has been reported to be significantly lowered by pre-administration of tocilizumab, due likely to the anti-inflammatory effect of the latter (102).

The effect of severity of inflammation on the action and disposition of the newly approved combination anti-COVID-19 drug, nirmatrelvir plus ritonavir (Paxlovid, Pfizer) also raises concerns over its proper use (Factors affecting CYP expression Section). The concentration of the active drug is very likely unpredictable due to the effect of the associated inflammation on the metabolizing enzymes.

COVID-19 initially appeared to spare children with only mild symptoms. However, it is now known that a small portion of children can develop a hyperinflammatory syndrome labeled as pediatric inflammatory multisystem syndrome, or cytokine storm. The effect of such an exaggerated expression of cytokines on pharmacotherapy is not known, but there is no reason to believe that it is negative (Age related considerations section).

In addition to the influence of inflammation on controlling blood pressure secondary to childhood obesity [Obesity section, Figure 9 (132)], there are some reports on the impact of inflammation on CYP metabolism in children. These reports are typically limited to acute care conditions such as the asthmatic children affected by Influenza B with small enrollment populations (22, 140). They have, nevertheless, provided some preliminary data regarding the effect of chronic inflammation on the action and disposition of drugs. One study with a sizable number of participants took data from 83 critically ill intensive care unit patients (2 months–17 years old) and created a pharmacokinetic model from the data to predict the alterations in drug metabolism potentially mediated by elevated cytokines (151). The study model illustrated that these patients might have experienced drug related toxicity due to prolonged and elevated drug concentration caused by CYP3A suppression. This suppression, the study proposes, is likely due to the presence of elevated CRP and IL-6 as the model showed the plasma midazolam concentration has been reported to be 2.7-fold higher at a CRP level of 300 mg/L compared to patients with CRP level of 10 mg/L (151).

Another pediatric study analyzed the general CYP expression of 51 children with sepsis, and 6 children with organ failure. The study found that, using antipyrine clearance as a marker, the children with sepsis had a 2-fold decline in CYP expression, and a 4-fold decline in the organ failure patients compared to controls (140). In patients with cystic fibrosis (CF), there is an elevation of neutrophils and increased concentrations of pro-inflammatory mediators in the airways. In another report, when the unbound fraction of drugs was assessed, CF patients did not differ significantly from healthy patients, and that changes in hepatic metabolic activity was selective in patients with CF (152).

It appears that childhood is not a risk factor for the imbalances due to inflammation. However, the above available data suggests that children are not exempt from inflammation induced altered drug action and disposition. In the meantime, Kawasaki syndrome and the recently reported COVID-related cytokine storm cases mainly involve children (153) which is bound to have consequences on the pharmacotherapy on account of increased cytokine expression.

Old age also is associated with inflammation (155), and the effect of such a chronic systemic change on pharmacotherapy, although has long been alarmed (156) is often overlooked. Studies mainly focus on pharmacokinetics with no pharmacodynamic data, thus extrapolating plasma concentrations to clinical outcomes. This is while with age the need for pharmacotherapy substantially increases. Through a rare study that included both pharmacokinetics and pharmacodynamics, Abernethy et al. (81) have shown that verapamil clearance is slowed down by aging resulting in increased drug concentration. However, similar to what has been discussed regarding patients with RA, Crohn’s disease and obesity, the effect of the drug to prolong P-R interval had diminished despite increased concentration (Figure 10). The blood pressure lowering effect of the drug was not significantly different between the elderly and young subjects despite different exposures. At the time, the authors were not able to explain their unexpected disconnect between pharmacokinetics and pharmacodynamics observation, The later data, however, is suggestive of simultaneous down regulation of proteins involved in metabolism and drug-receptor interaction. However, the severity of inflammation must be considered for choosing the right cardiovascular therapy regimen for elderly patients.

Bechet’s disease is characterized as a chronic inflammatory disorder that causes blood vessel inflammation throughout the body, typically controlled by colchicine (157). Goktas et al. compared 52 Bechet’s disease patients with 96 healthy volunteers to assess the genotype and phenotype of CYP2C9 by allele-specific PCR and delineating the ratio of losartan/metabolite ratio, respectively. They found a higher losartan/metabolite ratio in Bechet’s disease as compared with healthy subjects (1.75 vs. 1.02) suggestive of lower CYP2C9 activity in patients. The study ruled out CYP2C9 polymorphisms (157). The therapeutic outcomes of supressed CYPs expression on pharmacotherapy of drugs used to treat non-Bechet’s disease conditions of these patients is unknown mainly due to the scarcity of data stemming from unavailability of sufficient patients for clinical trials.

The pharmacodynamic impact of clozapine therapy during inflammation has not been well elucidated, however there have been case reports regarding toxicity seen with olanzapine and clozapine in patients with systemic inflammation (158, 159). In one case, a 54-year-old male, who was stabilized on olanzapine injections, developed post-injection delirium/sedation syndrome after taking his seventh olanzapine injection. He was brought into the emergency department and diagnosed with pharyngitis and bronchitis with a CRP rise from 18 to 179 mg/L after 48 h. This toxicity is believed to be mediated by altered metabolism of olanzapine via CYP1A1 suppression during the state of inflammation (160).

A similar observation has been made in four patients on clozapine who were admitted to hospital for clozapine related toxicity. Two of the cases had a hypersensitivity reaction to clozapine, while the other two had pneumonia. This resulted in the development of flu-like symptoms and clozapine related toxicities. All of the 4 cases had supratherapeutic clozapine plasma concentrations. The authors proposed that CYP modulation could be a source of toxicity due to clozapine’s influences on the plasma levels of several proinflammatory cytokines such as IL-6 and IL-8 and the inflammatory state that the patients had, potentially impacting CYP1A2 activity, the main clozapine metabolizing enzyme (159).

Another case presents a 23-year-old with schizophrenia admitted to the hospital for a gastrointestinal infection had a trough serum concentration of clozapine at admission of 9074 nmol/L, almost 4-fold the upper limit of the reference range. The patient however did not demonstrate any clozapine-related toxicity (159). The author proposed that the phenomenon was probably due to 1) a downregulation of CYP enzyme activities which primarily seems to be mediated by IL-6, during infection and inflammation and/or 2) an increase in AAG during infection and inflammation.