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Gastrointestinal Medications

From the Walter Reed Army Medical Center, Washington, DC, and the Dept. of Psychiatry, Univ. of Maryland Medical System. Dr. Sandson is Clinical Assistant Professor in the Dept. of Psychiatry at the Univ. of Maryland Medical System and Director of the Division of Education and Residency Training for the Sheppard Pratt Health System. He currently directs the Sheppard Pratt Psychopharmacology Consultation Service. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Dept. of Medicine, Walter Reed Army Medical Center, Washington, DC, and is Assistant Professor of Psychiatry, Uniformed Services Univ. of Health Sciences, Bethesda, MD. Dr. Cozza is co-author, along with Drs. Scott C. Armstrong and Jessica R. Oesterheld, of The Concise Guide to Drug Interaction Principles for Medical Practice (American Psychiatric Publishing, Inc., 2003). Send correspondence and reprint requests to Gary H. Wynn, M.D., Dept. of Psychiatry, Walter Reed Army Medical Center, Washington, DC. e-mail: ghwynn{at}gmail.com

ABSTRACT

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
Medications to address gastrointestinal disorders are among the most commonly dispensed somatic medications. The authors examine proton pump inhibitors, H₂ blockers, 5-HT₃ receptor-antagonists, and a few other drugs that are used to address this domain of medical concerns. The metabolic pathways, interactions with the P-glycoprotein transporter, and capabilities of inhibiting or inducing metabolic enzymes are elucidated for each drug. Specific drug–drug interactions with each agent are also detailed, including both psychotropic and non-psychotropic agents. Also, the article explores how different genotypic variants for specific cytochrome P450 enzymes have an impact on the effectiveness and likelihood of drug–drug interactions relating to specific gastro-intestinal medications.

INTRODUCTION

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
Gastrointestinal symptoms make up a significant portion of presenting somatic complaints, ranging from gastro-esophageal reflux disease (GERD) and hiatal hernias to irritable bowel disease and nausea associated with cancer therapy. Medication therapy for these disorders also varies widely, from centrally-acting antiemetics to nonabsorbable fiber products. This article will review the more frequently prescribed medications for gastrointestinal disorders and the possible drug–drug interactions associated with these therapies. The article covers the following: 1) proton pump inhibitors; 2) H₂ blockers and 5-HT₃ receptor-antagonists; and 3) other treatments for a variety of gastrointestinal disorders.

PROTON PUMP INHIBITORS

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
Proton pump inhibitors (PPIs) have become standard therapy in the treatment of GERD. PPIs work by blocking the gastric acid pump H⁺/K⁺-adenosine-triphosphatase (H⁺/K⁺-ATPase) and suppressing gastric acid secretion.¹ The five currently available PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Although all the PPIs are substituted benzimidazoles and have similar key pharmacokinetic parameters,² differences in their metabolic pathways can produce different drug–drug interaction concerns.

Esomeprazole, lansoprazole, and omeprazole are primarily metabolized by CYP 2C19 to a hydroxy metabolite and by CYP 3A4 to a sulphone metabolite.³ CYP2C19 is a polymorphic enzyme.⁴ The genotypes resulting from these 2C19 polymorphisms yield three phenotypic populations: extensive metabolizers (EMs), EMs with diminished activity, and poor metabolizers (PMs).⁵ Inhibitors and inducers affect EMs and PMs differently. CYP2C19 inhibitors such as fluvoxamine, ticlopidine, and ritonavir can result in significantly decreased metabolic activity in EMs, whereas PMs see little change. Similarly, EMs may be more affected by CYP2C19 inducers than are PMs. This may explain the large variation in results in some studies when CYP 2C19 activity is not phenotyped. Yu et al.⁶ studied EMs and PMs for CYP 2C19 when co-administered moclobemide (CYP 2C19-dependent metabolism) and omeprazole (CYP 2C19-inhibitor). EMs had extensive inhibition of moclobemide metabolism, whereas PMs had little variation in overall metabolism rates. Similarly, Yasui-Furukori et al.⁷ studied the effects of fluvoxamine (a CYP 2C19-inhibitor) on omeprazole (metabolized by CYP 2C19). In this study, EMs had a significant increase in omeprazole levels during administration of fluvoxamine, whereas PMs had little change in blood levels when fluvoxamine was co-administered.

Thus, an individual’s enzymatic genotype may be an important element in clinical decision-making, as the associated phenotypes clearly influence the likelihood and nature of drug–drug interactions when using PPIs. In this article, the effect of CYP 2C19 polymorphism will not be discussed further. However, this is a relevant concern when CYP2C19 substrates, inhibitors, and/or inducers are involved in potential drug–drug interactions.

Omeprazole (Prilosec®)
Now available in an over-the-counter (OTC) formulation, omeprazole was the first PPI to be approved for use in the United States, and it significantly altered the treatment of acid secretion-related disorders. Omeprazole is generally considered a very safe and effective medication, with a success rate of 80% in some studies. Although PPIs can result in hypertrophy of the parietal cells, no significant long-term negative side effects have been associated with treatment. Omeprazole is primarily metabolized by CYP 2C19 to both 5-O-desmethylomeprazole and 5-hydroxyomeprazole, and also by CYP 3A4 to 3-hydroxyomeprazole and omeprazole sulphone.⁸ These metabolites have not been shown to have antisecretory effects. Omeprazole also inhibits CYP 2C19⁹ and induces CYP 1A2,¹⁰ although this induction is currently thought to be weak. Studies specifically evaluating omeprazole’s impact on other medications have shown no effect or no clinical impact on metoprolol,¹¹ cerivastatin,¹² voriconazole,¹³ propranolol,¹⁴ coumadin (r-enantiomer),¹⁵ and theophylline¹⁶ co-administration. Medications that were adversely affected when co-administered with omeprazole included clozapine in non-smokers, cilostazol, proguanil, diazepam, and phenytoin. Mookhoek et al.¹⁷ retrospectively reviewed 13 patients on omeprazole and clozapine who were transitioned to pantoprazole and clozapine without alteration of their clozapine dose.^17,18 Plasma levels of clozapine, metabolized primarily by CYP 1A2 and secondarily by CYP 2C19, increased significantly (>100 mcg/l) in non-smokers, as compared with a slight decrease in plasma levels in smokers. Smoked tobacco is a much more potent inducer of CYP 1A2 than is omeprazole.¹⁹ Removal of omeprazole resulted in increased plasma levels for non-smokers, suggesting that the complete reversal of CYP 1A2 induction was a more powerful influence in the metabolism of clozapine than was the reversal of CYP 2C19 inhibition. However, since smokers continued to have CYP 1A2 induction via tobacco-smoking, the reversal of CYP2C19 inhibition resulting from discontinuing omeprazole was a greater influence than a slight loss of CYP 1A2 induction. These results suggest that adding omeprazole to clozapine may result in decreased plasma levels and require alteration to the dosing regimen. In other studies, cilostazol,²⁰ proguanil,²¹ diazepam, and phenytoin²² levels increased in the presence of omeprazole due to inhibition of CYP 2C19.

Many medications may affect omeprazole levels through inhibition or induction of CYP 2C19 and/or 3A4. Wang et al.²³ showed that St. John’s wort, a CYP 2C19 and 3A4 inducer, significantly decreased plasma concentrations of omeprazole. Omeprazole’s wide therapeutic margin and overall safety mean that the potential for clinically relevant drug–drug interactions affecting omeprazole levels are likely limited to increased side effects or therapeutic failure.

Lansoprazole (Prevacid®)
Lansoprazole is metabolized to 5-hydroxylansoprazole by CYP 2C19 and to lansoprazole sulphone by CYP 3A4.^24,25 Lansoprazole, similar to omeprazole, induces CYP 1A2 but has no known inhibitory effects. Multiple studies have looked at the potential for drug–drug interactions with lansoprazole. These studies have found no clinically significant effects when lansoprazole was co-administered with oral contraceptives,²⁶ phenytoin,²⁷ diazepam,²⁸ prednisone,²⁹ theophylline,³⁰ or coumadin.³¹ Compared with omeprazole, lansoprazole does not appear to alter significantly the levels of other drugs.³² However, when medications metabolized at CYP 1A2, such as clozapine, are co-administered with lansoprazole, close monitoring would be a prudent measure.

Rabeprazole (Aciphex®)
Rabeprazole is metabolized by CYP 2C19 to de-methylated rabeprazole and by CYP 3A4 to rabeprazole sulphone. Also, rabeprazole has significant non-enzymatic conversion to rabeprazole thioether. This relative lack of dependence on CYP 2C19 means that rabeprazole likely has more consistent efficacy across CYP 2C19 genotypes³³ as well as fewer drug–drug interactions. Rabeprazole is not known to inhibit or induce any metabolic enzymes.

Pantoprazole (Protonix®)
Pantoprazole, the only PPI available in intravenous form, is metabolized by CYP 2C19 to demethylated pantoprazole and by CYP 3A4 to pantoprazole sulphone. Pantoprazole has shown no appreciable interaction with the cytochrome P450 system.^34–36 (See Table 1 for a listing of drug effects on CYP450 enzymes). Individual studies evaluating possible interactions have shown no interaction between pantoprazole and carbamazepine,³⁷ diazepam,³⁸ nifedipine,³⁹ antipyrine,⁴⁰ digoxin,⁴¹ metoprolol,⁴² diclofenac,⁴³ or phenprocoumon.⁴⁴

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TABLE 1. Drug Effect on CYP450 Enzymes

Esomeprazole (Nexium®)
Esomeprazole, the S-enantiomer of omeprazole, is metabolized by CYP 2C19 to 5-hydroxyomeprazole and by CYP 3A4 to esomeprazole sulphone. Esomeprazole inhibits CYP 2C19 activity,⁴⁵ but it does not appear to induce CYP 1A2 as does omeprazole.⁴⁶

H2-BLOCKERS

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
H₂-receptor antagonists (H₂RAs) have a long history of use in the treatment of acid-secretion disorders. H₂RAs include cimetidine (Tagamet®), ranitidine (Zantac®), nizatidine (Axid®), and famotidine (Pepcid®). Of the four widely available H₂RAs, only cimetidine and ranitidine have significant metabolism by or interaction with hepatic enzymes. Famotidine appears to be a P-glycoprotein substrate, although studies exploring the possibility of interactions through inhibition or induction of this transporter have not been performed.

Ranitidine (Zantac®)
Ranitidine, an H₂-receptor antagonist available in an OTC formulation, is commonly prescribed for the treatment of hyperacidic states, such as peptic ulcer disease. Ranitidine is primarily oxidatively metabolized by flavin-containing monooxygenases (FMO3 and 5).⁴⁷ Minor contributions to ranitidine’s metabolism occur through CYP 2C19, 1A2, and 2D6. There is also some evidence that ranitidine is a substrate of the P-glycoprotein transporter, but no current evidence indicates that ranitidine has an inhibitory or inductive effect on P-glycoprotein transport. Ranitidine does weakly inhibit CYP 1A2, 2C9, 2D6, and 2C19, but has not shown inductive effects.⁴⁸ Studies of ranitidine co-administration with metoclopramide (metabolized by CYP 2D6)⁴⁹ and omeprazole (metabolized by CYP 2C19)⁵⁰ have shown increases in plasma levels, although the clinical significance of these increases has not been fully evaluated.

Cimetidine (Tagamet®)
Cimetidine, an OTC H₂-receptor antagonist, is a "pan-inhibitor" of the cytochrome P450 system. This inhibition results from the imidazole ring of cimetidine binding to the heme moiety of CYP, the binding site of oxygen, resulting in non-specific inhibition of CYP isoforms. Cimetidine significantly inhibits CYP 3A4, 2D6, 1A2, and 2C9.^48,51 Other enzymes may be affected, given cimetidine’s inhibitory mechanism, but clinical relevance has yet to be shown. Cimetidine has been documented as causing decreased clearance, unwanted side effects, and toxic levels of non-steroidal anti-inflammatory drugs, warfarin (metabolized by CYP 2C9), theophylline, and olanzapine (metabolized by CYP 1A2), as well as beta-blockers and tricyclic antidepressants (metabolized by CYP 2D6). In light of these data, patients should be asked about cimetidine use when initiating any other medications or when a drug–drug interaction is suspected.

5-HT₃ Receptor-Antagonist Anti-Emetics
The 5-HT₃ receptor antagonists (5HT₃RAs) block the action of serotonin through selective receptor antagonism, resulting in suppression of nausea and emesis from a variety of etiologies, including cancer chemotherapy and radiotherapy. The most prominent of the 5HT₃RAs are ondansetron, dolasetron, granisetron, palonosetron, and tropisetron. Ondansetron and granisetron are the earliest drugs in the 5HT₃RA class. Palonosetron is the most recent to have been approved by the FDA. Tropisetron is currently available in Europe, but not in the United States.

Because all of the 5HT₃RAs except granisetron are significantly metabolized by CYP 2D6, they are all susceptible to variable handling because of differences in CYP 2D6 genotypes in different individuals. In persons with the ultra-extensive (UEM) metabolism phenotype for CYP 2D6, the more rapid degradation of these 5HT₃RAs at standard doses has led to decreased efficacy.⁵²

Ondansetron (Zofran®)
Ondansetron’s oxidative metabolism occurs through CYP 1A2, 2D6, and 3A4.⁵³ The more complex nature of ondansetron’s metabolism means that inhibition of a single enzyme is less likely to alter ondansetron’s pharmacokinetics. Pan-inhibitors, such as ritonavir, or pan-inducers, such as rifampin, may cause significant alteration of ondansetron levels, but most medications are not likely to have a significant impact on plasma levels. Ondansetron also moderately inhibits CYP 1A2 and 2D6.⁵⁴

Granisetron (Kytril®)
Granisetron is primarily metabolized by CYP 3A4, and it is not known to inhibit or induce any hepatic enzymes.⁵⁵ Given granisetron’s dependence on CYP 3A4 for metabolism, inhibition or induction of this enzyme could theoretically result in significantly altered pharmacokinetics, resulting in toxicity or therapeutic failure, respectively. Potent CYP 3A4 inhibitors include nefazodone, ketoconazole, diltiazem, and grapefruit juice. Potent CYP 3A4 inducers include carbamazepine, phenytoin, and rifampin.

Dolasetron (Anzemet®)
Dolasetron is a pro-drug of hydrodolasetron. Dolasetron is rapidly converted to hydrodolasetron by carbonyl reductase. Hydrodolasetron, the active metabolite, is metabolized primarily by CYP 2D6, with a minor contribution from CYP 3A4. Hydrodolasetron has been shown to weakly inhibit CYP 2D6.⁵⁴ No reports of drug–drug interactions could be found in researching this article.

Palonosetron (Aloxi®)
Palonosetron is the most recent 5HT₃RA to be approved by the United States FDA. Considered to be a second-generation 5HT₃RA, palonosetron, like ondansetron, is metabolized by CYP 2D6, 3A4, and 1A2.⁵⁶ Palonosetron has shown no inhibition or induction of enzymatic activity. Given the multiple enzymatic pathways for the metabolism of palonosetron, drug–drug interactions are unlikely except in the face of pan-inhibition or robust enzymatic induction.

Tropisetron (Navoban®)
Tropisetron is currently available only in Europe. Tropisetron’s metabolism occurs through CYP 2D6.⁵⁷ Tropisetron is also a weak inhibitor of CYP 2D6. No documented interactions were found in researching this article.

OTHER GASTROINTESTINAL DRUGS

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
Alosetron (Lotronex®)
Alosetron was originally approved by the FDA in early 2000, but it was taken off the market in November 2000 because of serious side effects. The FDA reevaluated and reapproved alosetron in 2002, restricting its use to women with severe, diarrhea-predominant, irritable bowel syndrome (IBS). Alosetron is metabolized by CYP 3A4, 2C9, and 1A2, and it exerts a modest inhibitory effect on CYP 1A2.⁵⁸ Studies of alosetron co-administration with alprazolam,⁵⁹ fluoxetine,⁶⁰ theophylline,⁶¹ and low-dose combination oral contraceptives⁶² did not show an alteration in blood levels of the co-administered medications. The likelihood of drug–drug interactions with alosetron is low, given the multiple metabolic pathways and the weak nature of alosetron’s CYP 1A2 inhibition.

Aprepitant (Emend®)
Aprepitant, a neurokinin₁ receptor-antagonist, is used in combination with 5-HT₃ receptor antagonists and corticosteroids to prevent chemotherapy-induced nausea and vomiting. Aprepitant is metabolized primarily by CYP 3A4, with a minor contribution by CYP 1A2 and 2C19.⁶³ Aprepitant shows weak inhibition of CYP 3A4 during the first week of therapy.⁶⁴ This inhibition of CYP 3A4 is followed by a period of weak induction lasting an additional week, followed by no effect on enzymatic activity by Day 15 of therapy. Similarly, aprepitant modestly induces CYP 2C9 after several days of therapy. This inductive effect lasts for the first 2 weeks of therapy, after which no effect is seen.⁶⁵ Providers should be aware of the mild potential for drug–drug interactions during the initiation of therapy and provide monitoring as well as patient education.

Budesonide (Entocort®)
Budesonide is a synthetic corticosteroid used as an anti-inflammatory agent in the treatment of Crohn’s disease. Budesonide is metabolized primarily through CYP3A4,⁶⁶ with a minor metabolic role played by conjugation through a cytosolic sulfotransferase (SULT), dehydroepiandrosterone-sulfotransferase (DHEA-ST).⁶⁷ This metabolism occurs with both intestinal and hepatic CYP 3A4, resulting in a low oral bioavailability of 10% after first-pass metabolism.⁶⁸ Known CYP 3A4 inhibitors such as ketoconazole⁶⁹ and itraconazole⁷⁰ have been shown to significantly increase the plasma levels of budesonide. Patients initiated on budesonide treatment should be monitored for potential drug–drug interactions whenever CYP 3A4 inhibitors are co-administered.

Tegaserod (Zelnorm®)
Tegaserod is a selective serotonin 5-HT₄ receptor partial antagonist with promotile activity, used in the treatment of constipation and abdominal pain-predominant IBS. Tegaserod metabolism occurs primarily through pH-dependent hydrolysis in the stomach, with no significant metabolism occurring via the cytochrome P450 system.⁷¹ Tegaserod does inhibit CYP 1A2 and 2D6.⁷² Drugs with CYP 1A2 substrates, such as clozapine and olanzapine, as well as CYP 2D6 substrates, such as nortriptyline and metoprolol, may be at risk for drug–drug interactions when co-administered with tegaserod.

CONCLUSIONS

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 
There is a considerable breadth of drug–drug interaction relating to the use of the array of gastrointestinal medications. (Table 2, Table 3, and Table 4 list types of metabolism and effects.) The generally high therapeutic index of these agents makes life-threatening toxicity of gastrointestinal drugs unlikely. However, impairments of treatment efficacy and avoidable side effects capable of derailing otherwise-successful therapies are quite possibly outcomes of drug–drug interactions that affect blood levels of these agents. Also, these agents can precipitate drug–drug interactions in which toxicity and loss of efficacy with other agents is a significant concern. Similarly, genetic polymorphisms can exert an impact on the effectiveness and likelihood of drug–drug interactions when using these drugs. Prudent clinicians would be well-advised to keep these issues in mind when patients are taking a gastrointestinal drug.

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TABLE 2. Drug Metabolism and Effects

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TABLE 3. Type of Drug Metabolism

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TABLE 4. Drug, Enzyme Metabolism, and Effect

ACKNOWLEDGMENTS

 
Dr. Wise welcomes Neil B. Sandson, M.D., as new Section Editor, with the ongoing participation of Kelly L. Cozza, M.D., for the continuing Med-Psych Drug–Drug Interaction Update column. Dr. Sandson is Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland Medical System and Director of the Division of Education and Residency Training for the Sheppard Pratt Health System. He currently directs the Sheppard Pratt Psychopharmacology Consultation Service. He has also written The Drug Interactions Casebook: The Cytochrome P450 System and Beyond (American Psychiatric Publishing, Inc., 2003), as well as numerous articles on drug interactions and psychopharmacology. He lectures widely on the topics of drug–drug interactions, bipolar disorder, evidence-based psychiatry, and psychotic disorders. Dr. Sandson has been elected a Distinguished Fellow of the American Psychiatric Association.

REFERENCES

TOP ABSTRACT INTRODUCTION PROTON PUMP INHIBITORS H2-BLOCKERS OTHER GASTROINTESTINAL DRUGS CONCLUSIONS REFERENCES

 

1. Robinson M, Horn J: Clinical pharmacology of proton pump inhibitors. Drugs 2003; 63:2739–2754[CrossRef][Medline]
2. McColl K, Kennerly P: Proton pump inhibitors: differences emerge in hepatic metabolism. Digest Liv Dis 2002; 34:461–467[CrossRef]
3. Andersson T: Pharmacokinetics, metabolism, and interactions of acid pump inhibitors. Clin Pharmacokinet 1996; 31:9–26[Medline]
4. Chong E, Ensom M: Pharmacogenetics of the proton pump inhibitors: a systematic review. Pharmacother 2003; 23:460–471[CrossRef]
5. Klotz U, Schwab M, Treiber G: CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 2004; 95:2–8[Medline]
6. Yu K, Yim D, Cho J, et al: Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP 2C19. Clin Pharmacol Ther 2001; 69:266–273[CrossRef][Medline]
7. Yasui-Furukori N, Takahata T, Nakagami T, et al: Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes. Br J Clin Pharmacol 2004; 57:487–494[CrossRef][Medline]
8. Andersson T: Pharmacokinetics, metabolism, and interactions of acid pump inhibitors. Clin Pharmacokinet 1996; 31:9–26[Medline]
9. Ko J, Sukhova N, Thacker D, et al: Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispo 1997; 25:853–862[Abstract/Free Full Text]
10. Rost K, Fuhr U, Thomsen T, et al: Omeprazole weakly inhibits CYP1A2 activity in man. Int J Clin Pharm Ther 1999; 37:567–574[Medline]
11. Anderssson T, Lundborg P, Regardh C: Lack of effect of omeprazole treatment on steady-state plasma levels of metoprolol. Eur J Clin Pharm 1991; 40:61–65[CrossRef][Medline]
12. Sachse R, Ochmann K, Rohde G, et al: The effect of omeprazole pre- and co-treatment on cerivastatin absorption and metabolism in man. Int J Clin Pharm Ther 1998; 36:517–520[Medline]
13. Wood N, Tan K, Purkins L, et al: Effect of omeprazole on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56:56–61[CrossRef][Medline]
14. Henry D, Somerville K, Kitchingham G, et al: Propranolol steady-state pharmacokinetics are unaltered by omeprazole. Eur J Clin Pharmacol 1987; 33:369–373[CrossRef][Medline]
15. Andersson T: Omeprazole drug interaction studies. Clin Pharmacokinet 1991; 21:195–212[Medline]
16. Dilger K, Zhichang Z, Klotz U: Lack of drug interaction between omeprazole, lansoprazole, pantoprazole, and theophylline. Br J Clin Pharmcol 1999; 48:438–444[CrossRef][Medline]
17. Mookhoek E, Loonen A: Retrospective evaluation of the effect of omeprazole on clozapine metabolism. Pharm World Sci 2004; 26:180–182[CrossRef][Medline]
18. Frick A, Kopitz J, Bergemann N: Omeprazole reduces clozapine plasma concentrations. Pharmacopsych 2003; 36:121–123[CrossRef]
19. van der Weide J, Steijns LS, van Weelden MJ: The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 2003; 13:169–172[CrossRef][Medline]
20. Suri A, Branner S: Effect of omeprazole on the metabolism of cilostazol. Clin Pharmacokinet 1999; 37:S53-S59
21. Funck-Bretano C, Becquemont L, Leneveu A, et al: Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in-vivo results from the in-vitro experiments. J Pharmacol Exp Ther 1997; 280:730–738[Abstract/Free Full Text]
22. Gugler R, Jensen J: Omeprazole inhibits oxidative drug metabolism: studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. Gastroenterology 1985; 89:1235–1241[Medline]
23. Wang L, Zhou G, Zhu B, et al: St. John’s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharm Ther 2004; 75:191–197[CrossRef][Medline]
24. Delhotal-Landes B, Petite J, Flouvat B: Clinical pharmacokinetics of lansoprazole. Clin Pharmacokinet 1995; 28:458–470[Medline]
25. Katsuki H, Hamada A, Nakamura C, et al: Role of CYP 3A4 and CYP 2C19 in the stereoselective metabolism of lansoprazole by human liver microsome. Eur J Clin Pharmacol 2001; 57:709–715[CrossRef][Medline]
26. Fuchs W, Seenewid R, Klotz V: Lansoprazole does not affect the bioavailability of oral contraceptives. Br J Clin Pharmacol 1994; 38:376–380[Medline]
27. Karol M, Locke C, Cavanaugh J: Lack of pharmacokinetic interaction between lansoprazole and intravenously-administered phenytoin. J Clin Pharmacol 1999; 39:1283–1289[Abstract]
28. Lefebrve R, Flouvat B, Karolac-Tamisier S, et al: Influence of lansoprazole on diazepam plasma concentrations. Clin Pharmacol Ther 1992; 52:458–463[Medline]
29. Cavanaugh J, Locke C, Karol M: Lack of interaction of lansoprazole or omeprazole with prednisone. Am J Gastroenterol 1993; 88:1589
30. Dilger K, Zheng Z, Klotz U: Lack of drug interaction between omeprazole, lansoprazole, pantoprazole, and theophylline. Br J Clin Pharmacol 1999; 48:438–444[CrossRef][Medline]
31. Cavanaugh J, Winters E, Cohen A, et al: Lack of effect of lansoprazole on steady-state warfarin metabolism (abstract). Gastroenterology 1991; 100:A40
32. Gerson L, Triadafilopoulos G: Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol 2001; 13:611–616[CrossRef][Medline]
33. Horai Y, Kimura M, Furuie H, et al: Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP 2C19 genotypes. Aliment Pharmacol Ther 2001; 15:793–803[CrossRef][Medline]
34. Huber R, Hartman M, Bliesath H, et al: Pharmacokinetics of pantoprazole in man. Int J Clin Pharmacol Ther 1996; 34:185–194[Medline]
35. Fitton A, Wiseman L: Pantoprazole. Drugs 1996; 51:460–482[Medline]
36. Hartman M, Zech K, Bliesath H, et al: Pantoprazole lacks induction of CYP 1A2 activity in man. Int J Clin Pharmacol Ther 1999; 37:159–164[Medline]
37. Huber R, Bliesath H, Hartman M, et al: Pantoprazole does not interact with the pharmacokinetics of carbamazepine. Int J Clin Pharmacol Ther 1998; 36:521–524[Medline]
38. Gugler R, Hartman M, Rudi J, et al: Lack of pharmacokinetic interaction of pantoprazole with diazepam in man. Br J Clin Pharmacol 1996; 42:249–252[CrossRef][Medline]
39. Bliesath H, Huber R, Steinijans V, et al: Pantoprazole does not interact with nifedipine in man under steady-state conditions. Int J Clin Pharmacol Ther 1996; 34:S81-S85
40. De May C, Meineke I, Steinijans V, et al: Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction. Int J Clin Pharmacol Ther 1994; 32:98–106[Medline]
41. Hartman M, Huber R, Bliesath H, et al: Lack of interaction between pantoprazole and digoxin at therapeutic doses in man. Int J Clin Pharmacol Ther 1995; 33:481–485[Medline]
42. Koch H, Hartman M, Bliesath H, et al: Pantoprazole has no influence on steady-state pharmacokinetics and pharmacodynamics of metoprolol in healthy volunteers. Int J Clin Pharmacol Ther 1996; 34:420–423[Medline]
43. Bliesath H, Huber R, Steinijans V, et al: Lack of pharmacokinetic interaction between pantoprazole and diclofenac. Int J Clin Pharmacol Ther 1996; 34:152–156[Medline]
44. Ehrlich A, Fuder H, Hartman M, et al: Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man. Eur J Clin Pharmacol 1996; 51:277–281[CrossRef][Medline]
45. Li X, Andersson T, Ahlstrom M, et al: Comparison of inhibitory effects of the proton-pump inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Disp 2004; 32:821–827[Abstract/Free Full Text]
46. Andersson T, Hassan-Alin M, Hasselgran G, et al: Drug interaction studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet 2001; 40:523–537[CrossRef][Medline]
47. Chung W, Park C, Roh H, et al: Oxidation of ranitidine by flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol 2000; 84:213–220[CrossRef][Medline]
48. Martinez C, Albet C, Agundez J, et al: Comparative in-vitro and in-vivo inhibition of cytochrome P450 CYP 1A2, CYP 2D6, and CYP 3A4 by H₂–receptor antagonists. Clin Pharmacol Ther 1999; 65:369–376[CrossRef][Medline]
49. Leucuta A, Vlase L, Farcau D, et al: Pharmacokinetic interaction study between ranitidine and metoclopramide. Rom J Gastroenterol 2004; 13:211–214[Medline]
50. Leucuta A, Vlase L, Farcau D, et al: A pharmacokinetic interaction study between omeprazole and the H₂–receptor antagonist ranitidine. Drug Metabol Drug Interact 2004; 20:273–281[Medline]
51. Furuta S, Kamada E, Suzuki T, et al: Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine, and omeprazole. Xenobiotica 2001; 31:1–10[CrossRef][Medline]
52. Janicki PK: Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor-antagonists for postoperative nausea and vomiting. Med Sci Monit 2005; 11:RA322-328
53. Candiotti K, Birnbach D, Lubarsky D, et al: The impact of pharmacogenomics on postoperative nausea and vomiting. Anesthesiology 2005; 102:543–549[CrossRef][Medline]
54. Blower P: 5-HT₃–receptor antagonists and the cytochrome P450 system: clinical implications. Cancer 2002; 8:405–414
55. Watanabe Y, Nakai H, Hoshiai H: The effect of granisetron on in-vitro metabolism of doxorubicin, irinotecan, and etoposide. Curr Med Res Opin 2005; 21:363–368[CrossRef][Medline]
56. Stoltz R, Cyong J, Shah A, et al: Pharmacokinetic and safety evaluation of palonosetron, a 5-HT₃ receptor-antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol 2004; 44:520–531[Abstract/Free Full Text]
57. Kaiser R, Sezer O, Papies A, et al: Patient-tailored anti-emetic treatment with 5-HT₃ receptor-antagonists according to cytochrome P450 2D6 genotypes. J Clin Oncol 2002; 20:2805–2811[Abstract/Free Full Text]
58. Koch K, Corrigan B, Manzo J, et al: Alosetron repeat-dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors. Aliment Pharmacol Ther 2004; 20:223–230[CrossRef][Medline]
59. D’Souza D, Levasseur L, Nezamis J, et al: Effect of alosetron on the pharmacokinetics of alprazolam. J Clin Pharmacol 2001; 41:452–454[Abstract]
60. D’Souza D, Dimmitt D, Robbins D, et al: Effect of alosetron on the pharmacokinetics of fluoxetine. J Clin Pharmacol 2001; 41:451–458
61. Koch K, Ricci B, Hedayetullah N, et al: Effect of alosetron on theophylline pharmacokinetics. Br J Clin Pharmacol 2001; 52:596–600[CrossRef][Medline]
62. Koch K, Campanella C, Baidoo C, et al: Pharmacodynamics and pharmacokinetics of oral contraceptives co-administered with alosetron (Lotronex). Dig Dis Sci 2004; 49:1244–1249[CrossRef][Medline]
63. Sanchez R, Wang R, Newton D, et al: Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance-P receptor-antagonist Aprepitant. Drug Metab Disp 2004; 32:1287–1292[Abstract/Free Full Text]
64. Majumdar A, McCrea J, Panebianco D, et al: Effects of Aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther 2003; 74:150–156[CrossRef][Medline]
65. Shadle C, Lee Y, Majumdar A, et al: Evaluation of potential inductive effects of Aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004; 44:215–233[Abstract/Free Full Text]
66. Edsbacker S, Andersson T: Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn’s disease. Clin Pharmacokinet 2004; 43:803–821[CrossRef][Medline]
67. Meloche C, Sharma V, Swedmark S, et al: Sulfation of budesonide by the human cytosolic sulfotransferase, dehydroepiandrosterone-sulfotransferase (DHEA-ST). Drug Metab Disp 2002; 30:582–585[Abstract/Free Full Text]
68. Schwab M, Klotz U: Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet 2001; 40:723–751[CrossRef][Medline]
69. Seidegard J: Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of administration. Clin Pharmacol Ther 2000; 67:13–17
70. Raaska K, Niemi M, Neuvonen M, et al: Plasma concentrations of inhaled budesonide and their effects on plasma cortisol are increased by the P450 3A4-inhibitor itraconazole. Clin Pharmacol Ther 2002; 72:362–369[CrossRef][Medline]
71. Zhou H, Horowitz A, Ledford P, et al: The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects. J Clin Pharmacol 2001; 41:1131–1139[Abstract]
72. Appel-Dingemanse S: Clinical pharmacokinetics of tegaserod, a serotonin 5-HT₄ receptor partial agonist with promotile activity. Clin Pharmacokinet 2002; 41:1021–1042[CrossRef][Medline]

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