| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Sign In to gain access to subscriptions and/or personal tools.
|
|
|
|||||||
Sign In to gain access to subscriptions and/or personal tools. |
|||||||||
DRUG INTERACTIONS |
From Dr. Falk Pharma GmbH, Freiburg, Germany (Dr Dilger); Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany (Dr Fux, Mr Röck, Dr Mörike, Dr Gleiter); and Coordination Centre for Clinical Trials at University Hospitals Tübingen and Ulm, Tübingen, Germany (Dr Gleiter).
Address for correspondence: Christoph H. Gleiter, Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Otfried-Müller-Str. 45, D-72076 Tübingen, Germany; e-mail: christoph.gleiter{at}med.uni-tuebingen.de.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
-hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6β-hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%-100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.
Key Words: Budesonide • cortisol • CYP3A • metronidazole
Metronidazole is an N-substituted imidazole antibiotic that is active against a wide variety of anaerobic protozoal parasites and anaerobic bacteria. In contrast to other indications, in Crohn's disease, high doses of metronidazole (20 mg/kg per day) are used for prolonged periods up to several months.5 The suspected role of bacteria in the pathogenesis of Crohn's disease provides the rationale for using adjunctive antibiotics. Imidazole derivatives structurally related to metronidazole such as ketoconazole or itraconazole are strong inhibitors of CYP3A, causing a more than 5-fold increase in the area under the plasma concentration-time curve (AUC) of CYP3A substrates.6 Metronidazole may inhibit CYP3A according to in vitro data,7 but it has been shown that low-dose metronidazole (400 mg twice daily) did not affect the pharmacokinetics of the CYP3A substrate midazolam.8 However, 3 recent case reports describing (1) the elevation of tacrolimus trough concentrations (dual substrate of CYP3A and P-glycoprotein [P-gp]) by addition of 2 g metronidazole per day, (2) the occurrence of Torsades de Pointes due to coadministration of 1.5 g metronidazole per day and amiodarone (substrate of CYP3A), and (3) an indication for an unexpected drug interaction between metronidazole (25 mg/kg per day) and oral budesonide in a patient with Crohn's disease substantiated our decision to test the effect of high-dose metronidazole on the pharmacokinetics of oral budesonide.9-11
In a recent guidance document on drug interaction studies by the US Food and Drug Administration defining the best practices, budesonide is given as sensitive substrate of CYP3A.12 The drug is a newer synthetic glucocorticoid with high glucocorticoid receptor binding affinity and a low rate of systemic side effects because of low systemic bioavailability.13 Absolute bioavailability of oral budesonide is 10% due to extensive first-pass metabolism in gut and liver by CYP3A enzymes.14 The main metabolites formed via CYP3A are 6β-hydroxybudesonide and 16-hydroxyprednisolone.15 Moreover, budesonide is a substrate of the intestinal drug efflux pump, P-gp.16 Oral budesonide is approved for the treatment of mild to moderate exacerbations of Crohn's disease, the incidence of which has been shown to be increasing rapidly in Western countries.17,18
For safety reasons, it must be clarified if patients with Crohn's disease who are using the standard dosage of oral budesonide are at an increased risk of Cushingoid symptoms and other steroid-related side effects during treatment with metronidazole because of elevated systemic budesonide concentrations resulting from inhibition of biotransformation via CYP3A. Therefore, the primary aim of the study was to investigate the impact of 1.5 g metronidazole per day, given over 1 week, on the CYP3A-dependent metabolic profile of budesonide and that of endogenous cortisol. CYP3A catalyzes the transformation of cortisol to 6β-hydroxycortisol.19 The secondary aim was to study vice versa a possible effect of budesonide on the disposition of metronidazole due to a report on a significant reduction of metronidazole plasma concentrations in 6 patients with Crohn's disease by coadministration of the older synthetic glucocorticoid, prednisone.20
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Study Design
The investigation was conducted as a fixed-order study. In the morning on study days 1 and 9, a single oral dose of 3 mg budesonide was administered. On study days 2 to 8, each subject received 1.5 g metronidazole per day (divided into a morning and an evening dose). On study day 9, last metronidazole (750 mg) was given simultaneously with oral budesonide. To ensure compliance, each subject had to report to the study site for each drug intake (mouth check). Subjects were hospitalized the evening before study days 1, 8, and 9. After an overnight fast, a standardized lunch was served not until 4 hours after ingestion of the study drug(s), and intake of fluid was standardized over 8 hours. Pharmacokinetic profiling of budesonide was performed identically on study days 1 and 9 by determination of budesonide and the 2 CYP3A-dependent metabolites (6β-hydroxybudesonide, 16-hydroxyprednisolone) in plasma before and during 24 hours after drug intake. In detail, blood samples were collected just before and 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, and 24 hours after drug administration. Pharmacokinetic profiling of metronidazole was performed on study days 8 and 9 by measuring metronidazole in plasma; blood samples were collected just before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after drug administration. To prove that the dosing strategy was adequate to achieve steady state during the interaction, blood samples for trough concentrations of metronidazole were collected before each morning dosing on study days 6 to 8. On study days 1 and 9, urine was collected for 12 hours after dosing to determine urinary excretion of cortisol and 6β-hydroxycortisol. Plasma and urine were stored at -20°C until batch analysis.
Analytical Methods
Concentrations of budesonide, 6β-hydroxybudesonide, and 16-hydroxyprednisolone in plasma were determined by validated liquid chromatography tandem mass spectrometry as described previously.22 The mass-to-charge transition (m/z) was monitored at 489.2 to 339.2 for budesonide, 505.0 to 373.1 for 6β-hydroxybudesonide, 374.9 to 327.1 for 16-hydroxyprednisolone, and 492.8 to 375.2 for the internal standard (flunisolide). The lower limits of quantification in plasma were 0.1 ng/mL for budesonide and 6β-hydroxybudesonide and 0.5 ng/mL for 16-hydroxyprednisolone. Between-day and within-day coefficients of variation of quality controls were less than 15%. Concentrations of cortisol and 6β-hydroxycortisol in urine were determined by validated liquid chromatography tandem mass spectrometry. The mass-to-charge transition (m/z) was monitored at 421.1 to 331.2 for cortisol, 437.1 to 347.0 for 6β-hydroxycortisol, and 451.2 to 361.1 for the internal standard (dexamethasone). The lower limit of quantification was 1 ng/mL. Between-day and within-day coefficients of variation of quality controls were less than 10%. Concentrations of metronidazole in plasma were determined by standard high-performance liquid chromatography.23 The lower limit of quantification was 0.03 µg/mL. Between-day and within-day coefficients of variation of quality controls were less than 7%.
Pharmacokinetic and Pharmacodynamic Analyses
Standard model-independent methods were used to determine the pharmacokinetic parameters of interest (Kinetica Version 4.0, Thermo Electron Corporation, Philadelphia, Pennsylvania). Peak plasma concentration (Cmax) and time of Cmax (tmax) were taken directly from the plasma concentration-time curves. Areas under the plasma concentration-time curves covering different intervals (eg, AUC0-24 h) were determined by a combination of linear and logarithmic trapezoidal methods with extrapolation to infinity (AUC0-
). Terminal elimination half-life (t
) was calculated from the final slope of the log-linear concentration-time curve by least squares linear regression. Apparent oral clearance (CL/f = dose/AUC0-) and apparent volume of distribution (Vd/f = dose/[AUC0-·
]) were normalized for body weight. Peak trough fluctuation (PTF) of metronidazole plasma concentrations at steady state was derived from the equation PTF = 100·(Css,max - Css,min)/Css,av with Css,av = AUCss,0-12 h/12. Ratios of metabolite formation (AUCMet/AUCBudesonide, where Met is the CYP3A-dependent metabolite), such as AUC0-24 h of 6β-hydroxybudesonide to AUC0-24 h of budesonide, were used as indices of CYP3A activity. In addition, possible induction or inhibition of CYP3A enzymes by metronidazole was evaluated by measuring the cumulative amount of cortisol and 6β-hydroxycortisol excreted into the urine during the 12-hour collection period (Ae0-12 h); metabolic ratios (Ae6β-OH-cortisol/Aecortisol) were calculated in each subject.
Statistical Analysis
The study had a 94% power to detect a 20% difference in the plasma AUC of budesonide between study day 1 and study day 9 with a P value of less than .05. Sample size calculation was based on the coefficient of variation of the budesonide AUC in a previous study.22 Statistical analysis was performed by use of the software package GraphPad Instat (Version 3.05, GraphPad Software, Inc., San Diego, California). Wilcoxon matched pairs test was performed to compare pharmacokinetic/pharmacodynamic parameters between 2 different study days (eg, day 1 vs day 9). Two-sided P < .05 was regarded as statistically significant. According to the guidelines by the US Food and Drug Administration and the European Medicines Agency, the ratio of means with confidence intervals (CIs) of AUC and Cmax are the characteristics to determine equivalence for orally administered drugs; parametric testing using analysis of variance (ANOVA) on log-transformed data is the rule. Therefore, 90% CIs of the log-transformed parameters AUC0-24 h [AUCss,0-12 h] and Cmax [Css,max] of budesonide [metronidazole] before and during metronidazole [budesonide] administration were derived from the residual variance in multifactor ANOVA. The 90% CIs were based on the ratios of the population means (during/before comedication).
Ethics
The study protocol was approved by the ethics committee of the University Hospital Tübingen. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice. Written informed consent was obtained from each participant. The project is registered in the public trials registry sponsored by the US National Library of Medicine (www.clinicaltrials.gov, #NCT00338910
[ClinicalTrials.gov]
).
|
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Effect of Metronidazole on Budesonide and Cortisol
Pharmacokinetic parameters of budesonide and both CYP3A-dependent metabolites (mean ± SD or median with 95% CI) are given in Table I for comparison of baseline (study day 1) with the effect of high-dose metronidazole (study day 9). Wilcoxon testing did not reveal a significant difference between study day 1 and study day 9 in any of the parameters displayed (eg, AUC0- of budesonide: 4.88 ± 2.04 h·ng/mL vs 4.77 ± 2.11 h·ng/mL). Mean plasma concentration-time curves of budesonide, 6β-hydroxybudesonide, and 16-hydroxyprednisolone are shown in Figures 1, 2 and 3. Administration of 1.5 g metronidazole per day over 1 week did not affect the metabolism of budesonide via CYP3A: neither formation of 6β-hydroxybudesonide nor formation of 16-hydroxyprednisolone was significantly reduced by metronidazole (AUCMet/AUCBud: 2.1 ± 0.8 vs 2.0 ± 0.7, 6β-hydroxybudesonide; 8.3 ± 3.6 vs 9.1 ± 4.7, 16-hydroxyprednisolone; day 1 vs day 9; Figure 4). The 90% CI of AUC ratios of budesonide during metronidazole administration relative to baseline was 0.79 to 1.15, with the ratio of means being 0.95; the 90% CI of Cmax was 0.76 to 1.39, with the ratio of means being 1.03. In parallel to the metabolite kinetics of budesonide, CYP3A-dependent cortisol biotransformation was not significantly altered by intake of high-dose metronidazole over 1 week (Ae6β-OH-cortisol/Aecortisol: 7.6 ± 4.3 vs 6.7 ± 3.4, day 1 vs day 9; Figure 5).
|
|
|
|
|
Effect of Budesonide on Metronidazole
Pharmacokinetic parameters of metronidazole (mean ± SD or median with 95% CI) during steady-state dosing are given in Table II for comparison of baseline (study day 8) with the effect of a single dose of budesonide (study day 9). Mean plasma concentration-time curves of metronidazole are shown in Figure 6. Wilcoxon testing did not reveal a significant difference between study day 8 and study day 9 in peak concentrations (Css,max), tss,max, and PTF. AUCss,0-12 h and trough concentrations (Css,min) of metronidazole were significantly lower on study day 9 than on study day 8 (P < .05). The 90% CIs of both AUC and the Cmax ratio of metronidazole during budesonide administration relative to baseline were narrow (AUC: 0.91-1.00, Cmax: 0.90-1.08), with the ratios of means being near to 1.00 (AUC: 0.96, Cmax: 0.99).
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
-hydroxyprednisolone/budesonide have been validated previously as a marker of CYP3A activity using the prototype inducer rifampicin.24 Likewise, we found no significant effect by high-dose metronidazole on the formation of 6β-hydroxycortisol, which is an older validated test for evaluating induction and inhibition of CYP3A enzymes.19,25
A previous clinical trial in 10 healthy volunteers examining the CYP3A-altering properties of low-dose metronidazole (400 mg twice daily during 3 days) found no effect (midazolam plasma AUC ratio 0.93).8 As that study evaluated only the effect of low-dose metronidazole during a short course of treatment, that result does not exclude the possibility of a significant effect of metronidazole on CYP3A activity at a higher dosage or a longer duration of treatment as suggested in the newer case reports. Because testing for a possible drug interaction should maximize the possibility of finding an interaction, we used the maximum approved dose of metronidazole with a treatment period longer than 3 days for our systematic evaluation. However, no such drug interaction was found.
Interestingly, there are case reports describing an increase in plasma concentrations of dual substrates of CYP3A and P-gp with a narrow therapeutic range (tacrolimus, cyclosporine, carbamazepine, quinidine) by coadministration of metronidazole9,26-30; for example, 2 case reports document marked elevation in tacrolimus concentrations with the addition of metronidazole,9,26 and 3 case reports describe a harmful increase in cyclosporine concentrations in patients due to concurrent metronidazole.26,29,30 Some of the authors suggested that metronidazole should be added to the list of CYP inhibitors that can produce clinically important drug interactions.
The publication on the concurrent use of amiodarone and metronidazole highlighted a serious pharmacodynamic effect on the conduction system of the heart with positive dechallenge but did not provide information on drug concentrations in plasma for a precise interpretation.10 A study patient who had taken metronidazole (1.2 g per day during 12 days) until the evening before the first administration of oral budesonide showed remarkably delayed absorption of budesonide, which was no more observed 1 week later following withdrawal of metronidazole. Rechallenge was impossible in that subject because of resection of the ileum a short time later. The results of our study do not confirm the previous observation: lag time of budesonide was not prolonged by metronidazole. Altered intraluminal pH, delayed gastric emptying, or intestinal transit might explain delayed absorption of the enteric-coated budesonide preparation in an isolated case.11
We started our trial knowing that there is no simple relationship between in vitro inhibition potency of a substance and magnitude of drug interaction in the clinical setting. Some CYP3A inhibitors that did not demonstrate high in vitro potency had been shown to cause drug interactions of more than a 2-fold increase in AUC. These include CYP3A inhibitors causing mechanism-based irreversible inactivation (eg, clarithromycin, diltiazem).31 Unlike other human CYP enzymes, CYP3A offers the complicating factor that there appear to be 3 different substrate-binding types.32 In addition, the magnitude of an interaction on a CYP3A probe will depend on the amount of intestinal versus hepatic extraction with those drugs that have a greater intestinal extraction with larger interactions.31 Thus, very low bioavailability of oral budesonide at baseline might have increased several-fold in the face of CYP3A inhibition by high-dose metronidazole. At least a doubling of systemic exposure in the presence of an inhibitor was agreed to be reasonable for labeling action.1
Taking our data on CYP3A-dependent metabolite formation of budesonide and CYP3A-dependent cortisol biotransformation together, we assume that patients with Crohn's disease who are using the standard dosage of budesonide are not at an increased risk of Cushingoid symptoms or other steroid-related side effects during intake of high-dose metronidazole. This negative finding is important for clinicians and patients because antibiotics, metronidazole and ciprofloxacin, are the first line of medical therapy for fistulizing Crohn's disease.33 Moreover, metronidazole can also help to control colonic Crohn's disease or postoperative recurrence.34-36
One might then speculate about the discrepancy between case reports and results from clinical trials. Other investigators suggested that metronidazole may be a modulator or substrate of P-gp.8 To the best of our knowledge, there are no data available on this interesting issue. It is unknown if the effect of metronidazole on tacrolimus or the other dual substrates cited above is due to a change in activity of CYP3A, P-gp, or both. However, if metronidazole had significantly affected the drug efflux pump, we would have observed altered absorption or elimination characteristics of oral budesonide, which is also a dual substrate of P-gp and CYP3A. Thus, further studies are required for identifying whether metronidazole is a P-gp substrate and/or inhibitor.
In contrast to prednisone, budesonide did not augment the elimination of metronidazole. Whereas oral clearance of metronidazole was increased by 40% by concurrent prednisone, it was increased by 5% by concurrent budesonide. Trough concentrations but not peak concentrations of metronidazole decreased by approximately 7% due to concurrent budesonide. Because metronidazole is a drug without a narrow therapeutic range, this alteration in clearance was assessed to be clinically irrelevant. A correlation between serum concentration and effect as known in aminoglycosides does not exist for metronidazole.37 Metronidazole undergoes hepatic metabolism, forming 5 metabolites with markedly reduced or negligible antimicrobial activity; the involved drug-metabolizing enzymes are not known.38
In summary, our double drug interaction study with metronidazole and budesonide does not support generalizing conclusions from single case reports where addition of high-dose metronidazole has been associated with elevated plasma concentrations of substrates of CYP3A. High-dose metronidazole does not affect the pharmacokinetics of oral budesonide or vice versa.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Dr Dilger and Dr Fux contributed equally to this work.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Tucker GT, Houston JB, Huang SM. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential—toward a consensus. Clin Pharmacol Ther. 2001;70: 103-114.[CrossRef][Medline] [Order article via Infotrieve]
2. Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 1999;39: 1-17.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol. 1998;38: 389-430.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr. Torsades de Pointes occurring in association with terfenadine use. JAMA. 1990;264: 2788-2790.
5. Lal S, Steinhart AH. Antibiotic therapy for Crohn's disease: a review. Can J Gastroenterol. 2006;20: 651-655.[Web of Science][Medline] [Order article via Infotrieve]
6. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38: 41-57.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Maurice M, Pichard L, Daujat M, et al. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture. FASEB J. 1992;6: 752-758.[Abstract]
8. Wang JS, Backman JT, Kivistö KT, Neuvonen PJ. Effects of metronidazole on midazolam metabolism in vitro and in vivo. Eur J Clin Pharmacol. 2000;56: 555-559.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Page RL II, Klem PM, Rogers C. Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother. 2005;39: 1109-1113.
10. Kounas SP, Letsas KP, Sideris A, Efraimidis M, Kardaras F. QT interval prolongation and Torsades de Pointes due to a coadministration of metronidazole and amiodarone. Pacing Clin Electrophysiol. 2005;28: 472-473.[CrossRef][Medline] [Order article via Infotrieve]
11. Dilger K, Alberer M, Busch A, et al. Pharmacokinetics and pharmacodynamic action of budesonide in children with Crohn's disease. Aliment Pharmacol Ther. 2006;23: 387-396.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. US Food and Drug Administration. Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling. Available at: http://www.fda.gov/cder/guidance/index.htm#clinical%20pharmacology. Accessed August 10, 2007.
13. Papi C, Luchetti R, Gili L, Montanti S, Koch M, Capurso L. Budesonide in the treatment of Crohn's disease: a meta-analysis. Aliment Pharmacol Ther. 2000;14: 1419-1428.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Fedorak RN, Bistritz L. Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide. Adv Drug Deliv Rev. 2005;57: 303-316.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Jönsson G, Åström A, Andersson P. Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos. 1995;23: 137-142.[Abstract]
16. Dilger K, Schwab M, Fromm MF. Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein. Inflamm Bowel Dis. 2004;10: 578-583.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group. Gastroenterology. 1998;115: 835-840.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Armitage EL, Aldhous MC, Anderson N, et al. Incidence of juvenile-onset Crohn's disease in Scotland: association with northern latitude and affluence. Gastroenterology. 2004;127: 1051-1057.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Ged C, Rouillon JM, Pichard L, et al. The increase in urinary excretion of 6 beta-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol. 1989;28: 373-387.[Web of Science][Medline] [Order article via Infotrieve]
20. Eradiri O, Jamali F, Thomson AB. Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease. Biopharm Drug Dispos. 1988;9: 219-227.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Flockhart DA. Drug Interactions—Cytochrome P450 System. Available at: http://medicine.iupui.edu/flockhart/table.htm. Accessed July 3, 2007.
22. Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology. 2003;38: 196-202.[Web of Science][Medline] [Order article via Infotrieve]
23. Sirowej H, Bussemas HH, Harhoff F. Determination of drugs by HPLC with simultaneous UV-detection at two wavelengths. J Clin Chem Clin Biochem. 1985;23: 560.
24. Dilger K, Denk A, Heeg MH, Beuers U. No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology. 2005;41: 595-602.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Galteau MM, Shamsa F. Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol. 2003;59: 713-733.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
26. Herzig K, Johnson DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant. 1999;14: 521-523.[Web of Science][Medline] [Order article via Infotrieve]
27. Cooke CE, Sklar GE, Nappi JM. Possible pharmacokinetic interaction with quinidine: ciprofloxacin or metronidazole? Ann Pharmacother. 1996;30: 364-366.[Abstract]
28. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet. 1996;31: 198-214.[Web of Science][Medline] [Order article via Infotrieve]
29. Vincent F, Glotz D, Kreft-Jais C, Boudjeltia S, Duboust A, Bariety J. Acute kidney failure in a patient treated with cyclosporine A and metronidazole following kidney transplantation. Therapie. 1994;49: 155.[Web of Science][Medline] [Order article via Infotrieve]
30. Zylber-Katz E, Rubinger D, Berlatzky Y. Cyclosporine interactions with metronidazole and cimetidine. Drug Intell Clin Pharm. 1988;22: 504-505.[Medline] [Order article via Infotrieve]
31. Obach RS, Walsky RL, Venkatakrishnan K, Houston JB, Tremaine LM. In vitro cytochrome P450 inhibition data and the prediction of drug-drug interactions: qualitative relationships, quantitative predictions, and the rank-order approach. Clin Pharmacol Ther. 2005;78: 582-592.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
32. Kenworthy KE, Bloomer JC, Clarke SE, Houston JB. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br J Clin Pharmacol. 1999;48: 716-727.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
33. Bressler B, Sands BE. Review article: Medical therapy for fistulizing Crohn's disease. Aliment Pharmacol Ther. 2006;24: 1283-1293.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
34. Perencevich M, Burakoff R. Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis. 2006;12: 651-664.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
35. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology. 1995;108: 1617-1621.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
36. Sutherland L, Singleton J, Sessions J, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut. 1991;32: 1071-1075.
37. Cudmore SL, Delgaty KL, Hayward-McClelland SF, Petrin DP, Garber GE. Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis. Clin Microbiol Rev. 2004;17: 783-793.
38. Lamp KC, Freeman CD, Klutman NE, Lacy MK. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet. 1999;36: 353-373.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
