U N S O L IC I T E D E D I T O R I A L
Celiac Disease and Drug Absorption: Implications for Cardiovascular Therapeutics Ian Wang1,2 & Ingrid Hopper2,3 1 Monash University Medical School, Melbourne, Vic, Australia 2 CCRE Therapeutics, Monash University, Melbourne, Vic, Australia 3 Clinical Pharmacology Department, Alfred Hospital, Melbourne, Vic, Australia
Correspondence I. Hopper, Centre of Cardiovascular Research & Education in Therapeutics, Department of Epidemiology & Preventive Medicine, Monash University/The Alfred Centre, Melbourne, Vic 3004, Australia. Tel.: +61 3 9903 0042 Fax: +61 3 9903 0556 E-mail: [email protected]
doi: 10.1111/1755-5922.12094
Introduction Current prevalence of celiac disease is estimated to be around 1% in the general population of Europe [1] and the United States [2]. Cardiovascular disease has an even higher prevalence and is the leading cause of death in these regions, causing 46% of all deaths in the European Union [3] and 32% in the United States [4]. Given that many cardiovascular drugs are orally administered, absorption of these drugs may be significantly altered in celiac disease.
Cardiovascular Disease in Patients with Celiac Disease Large population studies have found celiac disease to be associated with significant increases in cardiovascular disease compared with the general population [5–7], although in other studies, no elevation in risk has been observed [8,9]. Celiac disease has been associated with 19% higher risk of incident ischemic heart disease [5] and with 43% higher all-cause mortality 1 year post-myocardial infarction compared with the general population [10]. Despite this, a more favorable risk factor profile has been seen in celiac individuals than that seen in the general population with ischemic heart disease, including less smoking, lower body mass index, lower serum cholesterol, and less extensive coronary disease at angiography [11]. The proportion of patients with celiac disease using different classes of cardiovascular drugs has been found to be similar or higher than that of comparator groups [7]; however, one study in patients with celiac disease following myocardial
ª 2014 John Wiley & Sons Ltd
infarction found lower prescription rates of statins and aspirin, and higher prescription rates of warfarin [11]. The reasons for the apparent increase in cardiovascular risk in the presence of favorable risk factors are not clear. Chronic inflammatory states are associated with atherosclerosis and cardiovascular disease [12,13], and elevated cardiovascular risk has been observed in other auto-immune conditions [14,15]. The presence of gluten in the bowel and resultant chronic inflammation causes increased expression of interferon-c and other cytokines in celiac disease, which are known to promote progression of atherosclerosis [16]. Reduction of inflammation with a glutenfree diet improves inflammatory markers and also markers of vascular impairment [17]. A further contributor may be hyperhomocysteinemia secondary to malabsorption of folic acid and vitamin B12, which is a recognized cardiovascular risk factor and associated with thrombosis [18].
Pathophysiology of Celiac Disease Patients with celiac disease have an intolerance to gliadin, an alcohol-soluble fraction of gluten, present in wheat, barley, and rye [19]. Gluten ingestion results in an immunologically mediated inflammatory response which damages the mucosa of the small bowel, predominantly the jejunum, resulting in maldigestion and malabsorption. This damage occurs when gliadin is presented by human leukocyte antigen (HLA) molecules to T helper cells which then mediate the inflammatory response. The resulting villous atrophy and destruction of the absorptive surface may alter absorption of orally administered medication.
Cardiovascular Therapeutics 32 (2014) 253–256
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Unsolicited Editorial
How Celiac Disease Affects Pharmacokinetics Celiac disease has a significant effect on drug absorption [20]. Due to its vast surface area compared with the stomach, most drug absorption occurs in the small intestine and in celiac disease, the surface area available for absorption is substantially reduced due to villous atrophy. The rate of gastric emptying is increased, delivering drug to the small intestine which can result in earlier absorption [21]. The majority of drugs are absorbed by passive diffusion. Nonionized molecules have greater lipid solubility and diffuse readily, while ionized molecules are less lipid soluble and cross membranes less effectively [22]. In celiac disease, the intraluminal pH of the small bowel is more alkaline [23], and this alters the ionization of the drug, which is determined by the drug’s acid dissociation constant (pKa)—the pH at which half the drug exists in the ionized form. Drugs with a high pKa are more nonionized in alkaline environments, favoring their absorption. Changes to the intraluminal pH also alter the gradient across the intestinal membrane which can affect passive diffusion. Villous atrophy can also result in the loss of cytochrome p450 enzymes located in the tips of the villi and reduce first-pass metabolism [24].
Evidence of Drugs Affected A small number of pharmacokinetic studies in celiac disease looking at cardiovascular drugs have been performed. Most were performed some decades ago. Drug absorption can be increased, delayed, reduced, or normal in celiac disease [25]. Drugs with increased absorption include propranolol [23,26,27], aspirin [28], methyldopa [29], and simvastatin [30]. Reduced absorption is seen with digoxin [31]. Beta-blockers are used in hypertension and atrial fibrillation for their blood pressure and heart rate lowering properties, and have been shown to improve mortality in patients with heart failure and acute myocardial infarction. There is wide variation in the pharmacology of beta blockers and lipid solubility in particular, with most beta-blockers having lower lipid solubility than propranolol [22]. Three studies found increased propranolol levels in patients with celiac disease compared with normal subjects. Parsons et al. [26] compared two beta-blockers with differing absorptive properties. Propranolol, which is highly lipid soluble, was compared with practolol, which is a water-soluble beta-blocker that does not undergo hepatic metabolism. Fourteen patients with celiac disease in remission on gluten-free diet were compared with ten normal subjects. The plasma concentration and area under the curve (AUC) for propranolol was significantly higher in celiac subjects when compared to normal subjects. This was attributed to an increased rate of diffusion across the abnormal jejunal mucosa of the lipid soluble drug (with earlier peak levels) and also reduced hepatic clearance through saturation of first-pass hepatic metabolism. The plasma practolol concentration was slightly reduced compared to normal subjects, which the authors interpreted as indicating impaired diffusion of water-soluble drugs in celiac disease. However, another potential factor which can alter drug absorption is that some water-soluble drugs, including beta-blockers in current use, are absorbed via transporters in the intestine [32]. Practolol has since been removed from the market due to
254
Cardiovascular Therapeutics 32 (2014) 253–256
severe side effects including conjunctival scarring, fibrosis, and metaplasia [33]. A follow-on study by Schneider et al. [27] found similar results, with increased plasma propranolol levels in the first four hours, but AUC was not increased. The authors questioned whether first-pass metabolism was saturated by the increased rate of absorption. Another study found that higher jejunal surface pH correlated with increased propranolol absorption and impaired folate absorption in celiac subjects compared with healthy controls [22]. Propranolol has been largely superseded in cardiovascular disease by beta-blockers with more targeted beta-receptor affinity and once daily dosing. Acetylsalicylic acid, or aspirin, is a lipid-soluble, acidic platelet inhibitor. Absorption occurs in the stomach and in the small intestine. Low-dose aspirin (75–150 mg) is used for secondary prevention of myocardial infarction and also to reduce thrombophilic risk in heart failure. Low-dose aspirin has not been specifically examined in celiac disease; however, one study investigated aspirin at analgesic doses (600 mg) [28]. Absorption of aspirin occurred earlier in the patients with celiac disease than in the healthy controls, but overall the amount absorbed was the same in both groups, and by 45 min, the salicylate concentrations were the same in both groups. This finding is counter-intuitive, as absorption of acidic substances is impaired in a high pH environment, and suggests that factors other than the pKa of lipid-soluble drugs may play a more prominent role in affecting absorption. The authors explain the earlier absorption by faster gastric emptying time delivering the aspirin to the small intestine earlier. It is difficult to say whether these altered pharmacokinetics have any clinical relevance with low-dose aspirin. Methyldopa is an alpha-adrenergic agonist used mostly in pregnancy-induced hypertension. It is predominantly absorbed from the gut with high first-pass metabolism by sulfate conjugation which is most likely to occur in the intestinal wall. Renwick et al. [29] showed elevated blood levels of methyldopa, with a near doubling of the peak plasma concentration and the AUC in patients with celiac disease compared with healthy controls. Urinary methyldopa was collected and surprisingly, showed no increase in the amount of drug absorbed in the patients with celiac disease. The authors’ explanation for this was a decrease in the distribution from plasma to tissues in celiac disease, which was consistent with the observation of no increase in pharmacological response to the drug in the celiac group. Simvastatin is an HMG-CoA reductase inhibitor which lowers cholesterol by blocking conversion of HMG-CoA to mevalonate, an early, rate-limiting step in cholesterol synthesis. Statins are absorbed from the intestine with extensive first-pass hepatic metabolism. They are used in primary and secondary prevention of myocardial infarction. An interesting study examined whether simvastatin absorption could be used as a surrogate marker to assess disease activity in celiac disease [30]. After a single 20 mg dose, mean serum simvastatin levels were significantly elevated in 18 untreated patients with celiac disease compared with 11 healthy controls (46 24 nM versus 19 11 nM, P < 0.005), while in 25 treated patients with celiac disease on a gluten-free diet, the mean simvastatin level was closer to normal (21 16 nM). A cut-off value of 24 nM for diagnosis of inadequately treated celiac disease was suggested. The authors proposed that the increase in serum simvastatin levels was explained
ª 2014 John Wiley & Sons Ltd
Unsolicited Editorial
by reduced first-pass metabolism with the loss of intestinal CYP3A4. Digoxin is a cardiac glycoside and is absorbed passively mostly in the duodenum and jejunum. Digoxin has a steroid structure similar to fat soluble vitamins, which are also poorly absorbed in patients with celiac disease. When used in atrial fibrillation, digoxin lowers ventricular rate at rest, and in heart failure, it modulates autonomic tone and is a positive inotrope. A study of participants with compensated congestive cardiac failure compared four patients with celiac disease with ten controls without celiac disease [31]. Steady state digoxin levels on a dose of 250 mcg daily were significantly reduced (P < 0.001) in the patients with celiac disease (mean 0.4 ng/mL) compared to controls (mean 1.3 ng/mL). Decreased intestinal absorption was the likely explanation, as similar capacity for renal excretion was found in both groups. Various blockers of the renin-angiotensin-aldosterone system including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, used in hypertension, ischemic heart disease, and heart failure, have not been studied. Nor have calcium channel blockers which are commonly used in cardiovascular disease. Additionally, new oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban which are used to reduce stroke risk in nonvalvular atrial fibrillation, and various fixed dose anti-platelet agents including dipyridamole, clopidogrel, ticlopidine, prasugrel, and ticagrelor also have not been studied in celiac disease.
Implications for Cardiovascular Drugs
celiac disease are sparse, particularly for the more recently developed drugs. For some drugs, the altered pharmacokinetics may have no clinical relevance, such as that seen with aspirin and methyldopa whereas for other drugs, including beta-blockers and other anti-hypertensive agents, plasma levels of drugs may be increased or decreased. The ability to measure blood pressure or heart rate allows a convenient way to confirm that the drug is working, although increased vigilance may be appropriate to ensure the drug is working over the full dosing period. There may be altered synergism between the agents with combination antihypertensive products as a result of altered absorption of individual components in celiac disease. Increased plasma levels of some drugs may increase the risk of side effects, for example with statins, and these should be enquired about carefully. When available, therapeutic drug monitoring should be used, such as with digoxin, and this should be pursued during remission as well as during flares. Anticoagulation in celiac disease deserves particular attention. Warfarin hypersensitivity can occur secondary to malabsorption of vitamin K [34]. No studies have investigated the pharmacokinetics of the NOACs in celiac disease, and monitoring of plasma drug levels, especially during initiation and flares, should be considered [35]. In summary, clinicians should be aware that the pharmacology of drugs may be altered in celiac disease, during both active and remission periods. The etiology of changes to pharmacokinetics is multifactorial and can be unpredictable. There is a need for a more significant evidence base to inform clinical practice in this particular patient group, as the clinical consequences of altered absorption may be significant.
Cardiovascular drugs are used commonly in patients with celiac disease and pharmacokinetic studies of cardiovascular drugs in
References 1. Mustalahti K, Catassi C, Reunanen A, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening
7. Wei L, Spiers E, Reynolds N, Walsh S, Fahey T, Macdonald TM. Association between coeliac disease and cardio-vascular disease. Aliment Pharmacol Ther 2008;27:514–519. 8. West J, Logan RF, Card TR, Smith C, Hubbard
disease in women. N Engl J Med 2000;342:836– 843. 13. Emerging Risk Factors Collaboration Coordinating Centre. Department of Public Health and Primary Care, University of
R. Risk of vascular disease in adults with
Cambridge, C-reactive protein concentration
diagnosed coeliac disease: a population-based
and risk of coronary heart disease, stroke, and
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mortality: an individual participant
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9. Grainge MJ, West J, Card TR, Holmes GK. Causes of death in people with celiac disease
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15. Yurkovich M, Vostretsova K, Chen W,
erythematosus: a meta-analysis of observational studies. Arthritis Care Res (Hoboken), 2014;66:608–616. 16. Mormile R. Celiac disease and ischemic heart disease: what is the link? J Clin Cell Immunol 2013;4:6. 17. De Marchi S, Chiarioni G, Prior M, Arosio E. Young adults with coeliac disease may be at
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ª 2014 John Wiley & Sons Ltd
Celiac Disease and Drug Absorption: Implications for Cardiovascular Therapeutics Ian Wang1,2 & Ingrid Hopper2,3 1 Monash University Medical School, Melbourne, Vic, Australia 2 CCRE Therapeutics, Monash University, Melbourne, Vic, Australia 3 Clinical Pharmacology Department, Alfred Hospital, Melbourne, Vic, Australia
Correspondence I. Hopper, Centre of Cardiovascular Research & Education in Therapeutics, Department of Epidemiology & Preventive Medicine, Monash University/The Alfred Centre, Melbourne, Vic 3004, Australia. Tel.: +61 3 9903 0042 Fax: +61 3 9903 0556 E-mail: [email protected]
doi: 10.1111/1755-5922.12094
Introduction Current prevalence of celiac disease is estimated to be around 1% in the general population of Europe [1] and the United States [2]. Cardiovascular disease has an even higher prevalence and is the leading cause of death in these regions, causing 46% of all deaths in the European Union [3] and 32% in the United States [4]. Given that many cardiovascular drugs are orally administered, absorption of these drugs may be significantly altered in celiac disease.
Cardiovascular Disease in Patients with Celiac Disease Large population studies have found celiac disease to be associated with significant increases in cardiovascular disease compared with the general population [5–7], although in other studies, no elevation in risk has been observed [8,9]. Celiac disease has been associated with 19% higher risk of incident ischemic heart disease [5] and with 43% higher all-cause mortality 1 year post-myocardial infarction compared with the general population [10]. Despite this, a more favorable risk factor profile has been seen in celiac individuals than that seen in the general population with ischemic heart disease, including less smoking, lower body mass index, lower serum cholesterol, and less extensive coronary disease at angiography [11]. The proportion of patients with celiac disease using different classes of cardiovascular drugs has been found to be similar or higher than that of comparator groups [7]; however, one study in patients with celiac disease following myocardial
ª 2014 John Wiley & Sons Ltd
infarction found lower prescription rates of statins and aspirin, and higher prescription rates of warfarin [11]. The reasons for the apparent increase in cardiovascular risk in the presence of favorable risk factors are not clear. Chronic inflammatory states are associated with atherosclerosis and cardiovascular disease [12,13], and elevated cardiovascular risk has been observed in other auto-immune conditions [14,15]. The presence of gluten in the bowel and resultant chronic inflammation causes increased expression of interferon-c and other cytokines in celiac disease, which are known to promote progression of atherosclerosis [16]. Reduction of inflammation with a glutenfree diet improves inflammatory markers and also markers of vascular impairment [17]. A further contributor may be hyperhomocysteinemia secondary to malabsorption of folic acid and vitamin B12, which is a recognized cardiovascular risk factor and associated with thrombosis [18].
Pathophysiology of Celiac Disease Patients with celiac disease have an intolerance to gliadin, an alcohol-soluble fraction of gluten, present in wheat, barley, and rye [19]. Gluten ingestion results in an immunologically mediated inflammatory response which damages the mucosa of the small bowel, predominantly the jejunum, resulting in maldigestion and malabsorption. This damage occurs when gliadin is presented by human leukocyte antigen (HLA) molecules to T helper cells which then mediate the inflammatory response. The resulting villous atrophy and destruction of the absorptive surface may alter absorption of orally administered medication.
Cardiovascular Therapeutics 32 (2014) 253–256
253
Unsolicited Editorial
How Celiac Disease Affects Pharmacokinetics Celiac disease has a significant effect on drug absorption [20]. Due to its vast surface area compared with the stomach, most drug absorption occurs in the small intestine and in celiac disease, the surface area available for absorption is substantially reduced due to villous atrophy. The rate of gastric emptying is increased, delivering drug to the small intestine which can result in earlier absorption [21]. The majority of drugs are absorbed by passive diffusion. Nonionized molecules have greater lipid solubility and diffuse readily, while ionized molecules are less lipid soluble and cross membranes less effectively [22]. In celiac disease, the intraluminal pH of the small bowel is more alkaline [23], and this alters the ionization of the drug, which is determined by the drug’s acid dissociation constant (pKa)—the pH at which half the drug exists in the ionized form. Drugs with a high pKa are more nonionized in alkaline environments, favoring their absorption. Changes to the intraluminal pH also alter the gradient across the intestinal membrane which can affect passive diffusion. Villous atrophy can also result in the loss of cytochrome p450 enzymes located in the tips of the villi and reduce first-pass metabolism [24].
Evidence of Drugs Affected A small number of pharmacokinetic studies in celiac disease looking at cardiovascular drugs have been performed. Most were performed some decades ago. Drug absorption can be increased, delayed, reduced, or normal in celiac disease [25]. Drugs with increased absorption include propranolol [23,26,27], aspirin [28], methyldopa [29], and simvastatin [30]. Reduced absorption is seen with digoxin [31]. Beta-blockers are used in hypertension and atrial fibrillation for their blood pressure and heart rate lowering properties, and have been shown to improve mortality in patients with heart failure and acute myocardial infarction. There is wide variation in the pharmacology of beta blockers and lipid solubility in particular, with most beta-blockers having lower lipid solubility than propranolol [22]. Three studies found increased propranolol levels in patients with celiac disease compared with normal subjects. Parsons et al. [26] compared two beta-blockers with differing absorptive properties. Propranolol, which is highly lipid soluble, was compared with practolol, which is a water-soluble beta-blocker that does not undergo hepatic metabolism. Fourteen patients with celiac disease in remission on gluten-free diet were compared with ten normal subjects. The plasma concentration and area under the curve (AUC) for propranolol was significantly higher in celiac subjects when compared to normal subjects. This was attributed to an increased rate of diffusion across the abnormal jejunal mucosa of the lipid soluble drug (with earlier peak levels) and also reduced hepatic clearance through saturation of first-pass hepatic metabolism. The plasma practolol concentration was slightly reduced compared to normal subjects, which the authors interpreted as indicating impaired diffusion of water-soluble drugs in celiac disease. However, another potential factor which can alter drug absorption is that some water-soluble drugs, including beta-blockers in current use, are absorbed via transporters in the intestine [32]. Practolol has since been removed from the market due to
254
Cardiovascular Therapeutics 32 (2014) 253–256
severe side effects including conjunctival scarring, fibrosis, and metaplasia [33]. A follow-on study by Schneider et al. [27] found similar results, with increased plasma propranolol levels in the first four hours, but AUC was not increased. The authors questioned whether first-pass metabolism was saturated by the increased rate of absorption. Another study found that higher jejunal surface pH correlated with increased propranolol absorption and impaired folate absorption in celiac subjects compared with healthy controls [22]. Propranolol has been largely superseded in cardiovascular disease by beta-blockers with more targeted beta-receptor affinity and once daily dosing. Acetylsalicylic acid, or aspirin, is a lipid-soluble, acidic platelet inhibitor. Absorption occurs in the stomach and in the small intestine. Low-dose aspirin (75–150 mg) is used for secondary prevention of myocardial infarction and also to reduce thrombophilic risk in heart failure. Low-dose aspirin has not been specifically examined in celiac disease; however, one study investigated aspirin at analgesic doses (600 mg) [28]. Absorption of aspirin occurred earlier in the patients with celiac disease than in the healthy controls, but overall the amount absorbed was the same in both groups, and by 45 min, the salicylate concentrations were the same in both groups. This finding is counter-intuitive, as absorption of acidic substances is impaired in a high pH environment, and suggests that factors other than the pKa of lipid-soluble drugs may play a more prominent role in affecting absorption. The authors explain the earlier absorption by faster gastric emptying time delivering the aspirin to the small intestine earlier. It is difficult to say whether these altered pharmacokinetics have any clinical relevance with low-dose aspirin. Methyldopa is an alpha-adrenergic agonist used mostly in pregnancy-induced hypertension. It is predominantly absorbed from the gut with high first-pass metabolism by sulfate conjugation which is most likely to occur in the intestinal wall. Renwick et al. [29] showed elevated blood levels of methyldopa, with a near doubling of the peak plasma concentration and the AUC in patients with celiac disease compared with healthy controls. Urinary methyldopa was collected and surprisingly, showed no increase in the amount of drug absorbed in the patients with celiac disease. The authors’ explanation for this was a decrease in the distribution from plasma to tissues in celiac disease, which was consistent with the observation of no increase in pharmacological response to the drug in the celiac group. Simvastatin is an HMG-CoA reductase inhibitor which lowers cholesterol by blocking conversion of HMG-CoA to mevalonate, an early, rate-limiting step in cholesterol synthesis. Statins are absorbed from the intestine with extensive first-pass hepatic metabolism. They are used in primary and secondary prevention of myocardial infarction. An interesting study examined whether simvastatin absorption could be used as a surrogate marker to assess disease activity in celiac disease [30]. After a single 20 mg dose, mean serum simvastatin levels were significantly elevated in 18 untreated patients with celiac disease compared with 11 healthy controls (46 24 nM versus 19 11 nM, P < 0.005), while in 25 treated patients with celiac disease on a gluten-free diet, the mean simvastatin level was closer to normal (21 16 nM). A cut-off value of 24 nM for diagnosis of inadequately treated celiac disease was suggested. The authors proposed that the increase in serum simvastatin levels was explained
ª 2014 John Wiley & Sons Ltd
Unsolicited Editorial
by reduced first-pass metabolism with the loss of intestinal CYP3A4. Digoxin is a cardiac glycoside and is absorbed passively mostly in the duodenum and jejunum. Digoxin has a steroid structure similar to fat soluble vitamins, which are also poorly absorbed in patients with celiac disease. When used in atrial fibrillation, digoxin lowers ventricular rate at rest, and in heart failure, it modulates autonomic tone and is a positive inotrope. A study of participants with compensated congestive cardiac failure compared four patients with celiac disease with ten controls without celiac disease [31]. Steady state digoxin levels on a dose of 250 mcg daily were significantly reduced (P < 0.001) in the patients with celiac disease (mean 0.4 ng/mL) compared to controls (mean 1.3 ng/mL). Decreased intestinal absorption was the likely explanation, as similar capacity for renal excretion was found in both groups. Various blockers of the renin-angiotensin-aldosterone system including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, used in hypertension, ischemic heart disease, and heart failure, have not been studied. Nor have calcium channel blockers which are commonly used in cardiovascular disease. Additionally, new oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban which are used to reduce stroke risk in nonvalvular atrial fibrillation, and various fixed dose anti-platelet agents including dipyridamole, clopidogrel, ticlopidine, prasugrel, and ticagrelor also have not been studied in celiac disease.
Implications for Cardiovascular Drugs
celiac disease are sparse, particularly for the more recently developed drugs. For some drugs, the altered pharmacokinetics may have no clinical relevance, such as that seen with aspirin and methyldopa whereas for other drugs, including beta-blockers and other anti-hypertensive agents, plasma levels of drugs may be increased or decreased. The ability to measure blood pressure or heart rate allows a convenient way to confirm that the drug is working, although increased vigilance may be appropriate to ensure the drug is working over the full dosing period. There may be altered synergism between the agents with combination antihypertensive products as a result of altered absorption of individual components in celiac disease. Increased plasma levels of some drugs may increase the risk of side effects, for example with statins, and these should be enquired about carefully. When available, therapeutic drug monitoring should be used, such as with digoxin, and this should be pursued during remission as well as during flares. Anticoagulation in celiac disease deserves particular attention. Warfarin hypersensitivity can occur secondary to malabsorption of vitamin K [34]. No studies have investigated the pharmacokinetics of the NOACs in celiac disease, and monitoring of plasma drug levels, especially during initiation and flares, should be considered [35]. In summary, clinicians should be aware that the pharmacology of drugs may be altered in celiac disease, during both active and remission periods. The etiology of changes to pharmacokinetics is multifactorial and can be unpredictable. There is a need for a more significant evidence base to inform clinical practice in this particular patient group, as the clinical consequences of altered absorption may be significant.
Cardiovascular drugs are used commonly in patients with celiac disease and pharmacokinetic studies of cardiovascular drugs in
References 1. Mustalahti K, Catassi C, Reunanen A, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening
7. Wei L, Spiers E, Reynolds N, Walsh S, Fahey T, Macdonald TM. Association between coeliac disease and cardio-vascular disease. Aliment Pharmacol Ther 2008;27:514–519. 8. West J, Logan RF, Card TR, Smith C, Hubbard
disease in women. N Engl J Med 2000;342:836– 843. 13. Emerging Risk Factors Collaboration Coordinating Centre. Department of Public Health and Primary Care, University of
R. Risk of vascular disease in adults with
Cambridge, C-reactive protein concentration
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