J Clin Pharmacol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Portolés, A.
Right arrow Articles by Moreno, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Portolés, A.
Right arrow Articles by Moreno, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

DRUG INTERACTIONS

Lack of Pharmacokinetic Interaction Between Omeprazole or Lansoprazole and Ivabradine in Healthy Volunteers: An Open-Label, Randomized, Crossover, Pharmacokinetic Interaction Clinical Trial

A. Portolés, MD, PhD, A. Calvo, MD, A. Terleira, MD, PhD, L. Laredo, MD, PhD, G. Resplandy, MD, C. Gorostiaga, MD, PhD and A. Moreno, MD, PhD

From the Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, Madrid, Spain (Dr Portolés, Dr Calvo, Dr Terleira, Dr Laredo, Dr Moreno); Laboratorios Servier, Madrid, Spain (Dr Gorostiaga); and Cardiovascular Division, Institut de Recherches Internationales Servier, Courbevoie Cedex, France (Dr Resplandy).

Address for reprints: Dr A. Portolés, Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, c/Prof. Martín Lagos s/n, 28040 Madrid, Spain; e-mail: aportoles.hcsc{at}salud.madrid.org.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The effects of omeprazole and lansoprazole (CYP3A4 inhibitors) on the pharmacokinetics of a single dose of ivabradine (metabolized via CYP3A4) and its active metabolite (S18982) were assessed. Pharmacodynamics and safety were secondary objectives. An open-label, randomized, crossover, phase I, pharmacokinetic interaction design was used. Volunteers received a single oral dose of ivabradine (10 mg), were randomized to receive either omeprazole (40 mg) or lansoprazole (60 mg) for 5 days, and were administered an ivabradine dose on the sixth day. Crossover was performed after washout. Pharmacokinetic parameters for ivabradine did not vary significantly after omeprazole (Cmax: 45.0 ± 36.6 vs 42.7 ± 27.6 ng/mL, P = .98; AUC: 128 ± 87 vs 126 ± 63 ng/mL, P = .82) or lansoprazole administration (Cmax: 45.0 ± 36.6 vs 41.3 ± 29.4 ng/mL, P = .70; AUC: 128 ± 87 vs 123 ± 50, P = .73). Analyses of S18982 pharmacokinetic parameters showed similar results. Coadministration of either omeprazole or lansoprazole did not significantly affect the pharmacokinetics of a single dose of ivabradine. No pharmacodynamic interaction or safety concerns were evidenced.

Key Words: pharmacokinetics • interaction • ivabradine • omeprazole • lansoprazole • inhibition • healthy volunteers • clinical trial

Ivabradine (S16257 [GenBank] ) is a novel, heart rate–lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Its activity provides pure heart rate reduction at rest and during exercise, which improves myocardial oxygen balance and increases coronary perfusion without any relevant influence on conduction, contractility, ventricular repolarization, or blood pressure.1,2 The anti-ischemic efficacy and the safety of ivabradine have been demonstrated in patients with stable angina pectoris.3,4 Mild and transient visual symptoms, mainly phosphene-like events, have been reported and were generally well tolerated.

The metabolic clearance of ivabradine accounts for about 80% of its total clearance, with the other 20% corresponding to renal clearance. Only CYP3A4 is involved in ivabradine's metabolism, so numerous potential interactions can therefore arise with CYP3A4 inhibitors and inducers. Three major pathways are involved: cleavage reactions by N-dealkylation, leading to inactive metabolites; O-desmethylation, mono- or di-hydroxylation, and dehydrogenation, leading to either inactive or active metabolites that have insufficiently high plasma concentrations to contribute to the pharmacological effect; and N-desmethylation, leading to the major active metabolite S18982. This N-desmethylated S18982 is also a CYP3A4 substrate.5 Both in vitro and in vivo data have shown that ivabradine is unlikely to influence the pharmacokinetics or pharmacodynamics of other CYP3A4 substrates.

Proton pump inhibitors are often prescribed concomitantly with other agents and are used as long-term maintenance therapy to prevent recurrence of peptic ulcers or erosive reflux esophagitis. They are extensively metabolized by several human cytochrome P450 enzymes and are potential inducers/inhibitors themselves.6-8 Therefore, it is important to elucidate the potential for drug interactions with CYP450 substrates.

The objective of this study was to evaluate and compare the pharmacokinetics of ivabradine during multiple-dose administration of omeprazole or lansoprazole. In addition, the safety of concomitant administration of these agents was examined.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Six male and 6 female healthy white volunteers were enrolled after having met inclusion criteria and passed exclusion criteria. Healthy subjects were selected as the target population, assuming that a pharmacokinetic interaction would be predictive of a pharmacokinetic interaction in patients. The primary objective of this study was to explore a potential pharmacokinetic interaction. In this context, healthy volunteers appeared to be the population in which variability could be more effectively minimized, allowing for differences between administration conditions to be detected more accurately, while valuable exploratory data regarding secondary objectives could also be extracted.

Key inclusion criteria included age between 18 and 40 years, 12-lead electrocardiogram (ECG) within normal standards (QTc interval ≤450 msec [male subjects]; ≤470 msec [female subjects]), a body mass index below or equal to 30 kg/m2, negative anti–Helicobacter pylori antibodies, and normal hematology and biochemistry blood and urine analyses. Only subjects with a heart rate (at rest) ≥50 beats/min were included. A negative result for a quick test for beta-HCG was required, and an effective contraception method during the study was also compulsory for female subjects. Negative results on urine drug screen were required within 2 weeks before study participation.

Key exclusion criteria included personal or family history of long QT syndrome, acute or chronic disease, and regular use of medication. Further exclusion criteria were a personal history of H. pylori infection, hypersensitivity or photosensitivity to any drug, smoking, intention to donate blood or to participate in another study for the following months, or any clinically relevant abnormalities, including vital signs.

Subjects received no medication for 2 weeks prior to inclusion in the study (4 weeks in the case of CYP3A4 inducers or inhibitors) until the end of the study. Subjects were also free from stimulants (eg, coffee and tea), nicotine, and nonpharmacological liver inducers or inhibitors; strenuous physical exercise was to be avoided on the 3 days before inclusion and throughout the study.

Study Drugs
Ivabradine (10-mg tablets) was to be taken orally during a standard breakfast, as a single dose, whereas 40 mg of omeprazole (20-mg capsules) and 60 mg of lansoprazole (30-mg tablets) were to be taken once a day, 30 minutes before breakfast. All treatments were supplied by Servier Laboratories (Berkshire, UK); the proton pump inhibitors were commercially available formulations.

Design
An open-label, randomized, crossover, 3-period, phase I, pharmacokinetic interaction design was used. An open design was chosen because the effect of omeprazole and lansoprazole on the pharmacokinetics of ivabradine was the main objective of this exploratory study. The study was not confirmatory in nature, and the lower variability of a crossover design allowed a reduced sample size. The treatment sequences were assigned at random with stratification by sex. Considering the exploratory nature of the study, the analyses were essentially descriptive.

The study was performed according to the rules for good clinical practice (International Conference on Harmonization) and was authorized by the Ethics Committee of the Hospital Clínico San Carlos (HCSC) and by the AEMPS (Spanish agency on medicines and sanitary products). The ethics principles of the Declaration of Helsinki and its further revisions were observed, with written informed consent given by each subject after protocol approval.


Figure 1
View larger version (5K):
[in this window]
[in a new window]
  		Figure 1. Study design schema.

 
Subjects were selected 1 to 15 days before the start of the treatment (day –15 to day –1). They received a single oral dose of ivabradine (10 mg) and were randomized to receive either omeprazole (40 mg) or lansoprazole (60 mg) for 5 days. On the sixth day, a single dose of ivabradine was administered. After an 8-day washout period, the volunteers were crossed over to the alternate regimen (see Figure 1). The sequences of treatment were assigned according to a randomization list (stratified by sex) designed by the Biometrics Department of the Institut de Recherches Internationales Servier (IRIS).

All study drugs were administered under medical supervision with 250 mL of water at room temperature under fasting conditions. Subjects were admitted to the unit for about 24 hours the night before each administration of ivabradine (day 0, day 6, and day 19).

Blood sampling for pharmacokinetic monitoring of ivabradine and metabolite in plasma was collected prior to each administration of ivabradine, as well as at 11 time points up to 24 hours at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours.

Safety was monitored by collecting 12-lead ECG parameters at rest (PR, QRS, RR, and QT intervals; QTc; ST segment; rhythm or other abnormalities) and blood pressure during the inclusion period, prior to each administration of ivabradine, 3 hours and 24 hours after ivabradine intake, and prior to each administration of lansoprazole or omeprazole. Safety measurements also included recording of adverse events and other vital signs throughout the study, as well as chemistry/hematology/urinary analyses at the inclusion period and after completing treatment.

Pharmacodynamics (heart rate at rest) was evaluated as a secondary objective at the inclusion period, prior to each ivabradine administration, 3 hours and 24 hours after ivabradine intake, and prior to each administration of lansoprazole or omeprazole.

Assay
The assay for S16257 [GenBank] and S18982 previously had been validated. Plasma samples (1 mL) were stored at –20°C until assayed by a liquid-solid extraction followed by specific high-performance liquid chromatography (HPLC) analysis using a C8 column with fluorescence detection.9

Calculations of concentrations were performed by a least squares linear regression model using a 1/C2 weighting, with Excel 5.0 Microsoft and Millennium (Waters) software.

Data Analyses
A database was created for data management and analyses on demographic, safety, and activity using a proprietary clinical data management system developed by IDDI (Brussels, Belgium). The Type I error {alpha} was set at 5% for all statistical tests.

Pharmacokinetic Analysis
Data for concentration in plasma (C) versus time (t) for both ivabradine (S16257 [GenBank] ) and S18982 were analyzed by noncompartmental methods at the Hospital Clínico San Carlos (HCSC, Madrid, Spain). The pharmacokinetics of the compounds were characterized, as appropriate, using the WinNonlin Pro software (release 3.1). The highest observed concentration in plasma and the corresponding sampling time were defined as Cmax and tmax, respectively. The elimination rate constant ({lambda}z) was estimated by means of linear regression analysis of the log-linear part of the time-concentration profile, and t1/2 was defined as the apparent terminal half-life, calculated as (ln2)/{lambda}z. The area under the concentration-time curve (AUC) was estimated by use of the trapezoidal rule from time 0 to 12 hours (AUC12) and 24 hours (AUC24), up to the last measurable concentration (AUClast) and with extrapolation to infinity (AUC{infty}). The apparent total clearance (CL/F) for S16257 [GenBank] and the S18982 to S16257 [GenBank] AUC{infty} ratio were also calculated.

Statistical Analysis
Descriptive statistics (mean, standard deviation, median, range) for the Cmax, tmax, AUC12, AUC24, AUClast, AUC{infty}, and t1/2 of S16257 [GenBank] and S18982 were performed using WinNonlin Pro (release 3.1). Statistical analyses of pharmacokinetic parameters were carried out using the software Tryarcus. Comparison between ivabradine alone (I) versus ivabradine + omeprazole (I + O) and ivabradine alone (I) versus ivabradine + lansoprazole (I + L) values for AUC (AUC12, AUC24, AUClast, AUC{infty}), Cmax, and Cl/F was determined using the paired-data Student t test. The 95% confidence interval of the geometric mean ratio (I + O)/I or (I + L)/I for these parameters was calculated. The 95% confidence intervals of the difference between the ratio S18982 to S16257 [GenBank] AUC{infty} under ivabradine and the ratio S18982 to S16257 [GenBank] AUC{infty} under coadministration of ivabradine and omeprazole or lansoprazole were also calculated. The a priori level of significance was P = .05.

Given the discrete and nonparametric nature of tmax, the comparison between (I) and (I + O) or (I + L) for tmax was performed using the Wilcoxon signed rank test.

Descriptive statistics (mean, standard deviation, and range) for heart rate changes at rest were performed by treatment and period first, then by treatment only, in the per protocol population. The differences between mean heart rate at the beginning of periods 2 and 3 (before receiving treatment with either omeprazole or lansoprazole) were compared by analysis of variance (ANOVA).

Descriptive statistics for 12-lead ECG parameters, blood pressure, adverse events, treatment-emergent adverse events, biochemistry/hematology/urinary parameters, and concomitant treatments were provided. Qualitative variables were described by number and percentage of subjects, whereas quantitative variables were described by mean, standard deviation, median, and range.

A sample size of 12 was chosen because the crossover design allowed a reduced sample size and because the study was not considered confirmatory in nature but had the explorative aim to investigate the pharmacokinetic, pharmacodynamic, and safety parameters of coadministered ivabradine and omeprazole or lansoprazole. Data from all participants who received at least 1 dose of a given medication were included in the safety analyses for that medication. All randomized subjects having completed the study without any protocol deviation affecting the main activity criterion were included in the per protocol set, and all randomized subjects were included in the randomized set.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Pharmacokinetics
The 12 subjects evaluated were between 21 and 27 years old (mean ± SD = 24.2 ± 2.1 years), and their body mass index was between 19.1 and 29.6 kg/m2 (mean ± SD = 24.1 ± 3.7 kg/m2) (Table I). No clinically significant differences between treatment sequence groups were observed for any of the demographic or baseline characteristics. No subjects were excluded from the selected population, from the randomized population, or from the per protocol population.


View this table:
[in this window]
[in a new window]
  		Table I Demographic Data—Included Population (n = 12)

 


Figure 2
View larger version (7K):
[in this window]
[in a new window]
  		Figure 2. Mean ivabradine plasma concentration-time profiles obtained after a single oral ivabradine (N) administration and after coadministration with omeprazole (O) or lansoprazole (L) following repeated administration of omeprazole or lansoprazole.

 


Figure 3
View larger version (7K):
[in this window]
[in a new window]
  		Figure 3. Mean S18982 plasma concentration-time profiles obtained after a single oral ivabradine (N) administration and after coadministration with omeprazole (O) or lansoprazole (L) following repeated administration of omeprazole or lansoprazole.

 

No participant received any concomitant medication during the study that could be expected to affect study outcome.

Mean ivabradine and S18982 plasma concentrationtime profiles obtained after a single oral ivabradine administration and after coadministration with omeprazole or lansoprazole following repeated administration of omeprazole or lansoprazole are displayed in Figures 2 and 3. Ivabradine and S18982 concentrations at each sampling time were similar for the 3 treatment regimens. After administration, ivabradine concentrations rose rapidly to reach a maximum within 1 hour and then followed a monoexponential decline.

Pharmacokinetic parameters for ivabradine after a single administration of ivabradine alone and after coadministration with omeprazole or lansoprazole are reported in Table II, along with the results of the statistical analysis.


View this table:
[in this window]
[in a new window]
  		Table II Pharmacokinetic Parameters of Ivabradine After Single Oral Administration of Ivabradine 10 mg Alone or Coadministered With Omeprazole (40 mg) or Lansoprazole (60 mg) Following Repeated Administration of Omeprazole (40 mg qd) or Lansoprazole (60 mg qd)

 

Administration of omeprazole or lansoprazole did not produce any statistically significant effect on ivabradine AUC (AUC12, AUC24, AUClast, AUC{infty}) or Cmax. The mean ratio and 95% confidence intervals for these log-transformed parameters were within the 80% to 125% bioequivalence limits. There were no statistically significant differences for tmax, and the values obtained for t1/2 were similar after treatment with lansoprazole or omeprazole, although no statistical test had been planned.

The corresponding parameters for S18982 are summarized in Table III. No statistically significant difference between regimens was found for any of the pharmacokinetic parameters.


View this table:
[in this window]
[in a new window]
  		Table III Pharmacokinetic Parameters of S18982 After Single Oral Administration of Ivabradine 10 mg Alone or Coadministered With Omeprazole (40 mg) or Lansoprazole (60 mg) Following Repeated Administration of Omeprazole (40 mg qd) or Lansoprazole (60 mg qd)

 

No statistically significant difference in the S18982/S16257 AUC{infty} ratio was evidenced after repeated administration of omeprazole or lansoprazole (Table IV).


View this table:
[in this window]
[in a new window]
  		Table IV Comparison of the Differences in the AUC{infty} S18982/AUC{infty} S16527 Ratio Obtained After Ivabradine Alone Versus Ivabradine + Omeprazole or Ivabradine + Lansoprazole Versus Ivabradine Alone

 

Pharmacodynamics
The evolution over time of mean heart rate at rest before and after a single dose of ivabradine alone and after coadministration with omeprazole or lansoprazole is displayed in the per protocol population in Figure 4 and Table V (all periods pooled). Ivabradine induced a clear decrease in mean heart rate 3 hours after intake, by 5 to 8 bpm on average, regardless of coadministration with omeprazole or lansoprazole.


Figure 4
View larger version (11K):
[in this window]
[in a new window]
  		Figure 4. Evolution over time of mean heart rate at rest before and after a single dose of ivabradine and after coadministration with omeprazole or lansoprazole (average evolution profiles (mean ± SD per protocol population / pooled data).

 

View this table:
[in this window]
[in a new window]
  		Table V Evolution Over Time of Mean Resting Heart Rate (12-Lead Electrocardiogram [ECG]) Before and After Single Administration of Ivabradine (10 mg) and After Single Coadministration of Ivabradine (10 mg) + Omeprazole (40 mg) or Lansoprazole (60 mg) Following Repeated Administration of Omeprazole or Lansoprazole, by Treatment per Protocol Population (n = 12)

 

Safety Evaluation
No individual heart rate was below 45 bpm throughout the study. Ivabradine, omeprazole, and lansoprazole, given alone or in combination, were well tolerated by all subjects participating in the study.

A total of 6 treatment-emergent adverse events were reported during the study, all of which were mild or moderate. Two adverse events (eye pain) were reported after treatment with ivabradine + omeprazole, and the rest were reported after coadministration of ivabradine + lansoprazole (1 subject experienced postural hypotension, 2 subjects experienced abdominal pain, and another 1 experienced visual symptoms). No serious adverse events were reported.

No clinically or statistically significant differences were found between the 3 treatment regimens for any clinical laboratory parameter, for 12-lead ECG parameters, or for a mean change from baseline for any vital sign parameter.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Because proton pump inhibitors are widely used for the treatment of acid-related gastrointestinal disorders, concomitant prescription of ivabradine and omeprazole or lansoprazole, 2 of the most frequently used proton pump inhibitors, is likely to be prevalent.

Ivabradine, together with most proton pump inhibitors, undergoes metabolic conversion by cytochrome P450, including CYP 3A4. Most proton pump inhibitors, particularly omeprazole and lansoprazole, have been shown to modify other drugs' metabolism.10-13 According to a validated experimental in vitro model enabling the prediction of drug-drug interaction by concomitant incubation of human hepatic microsomes with ivabradine and various test drugs, the interaction of the 2 proton pump inhibitors, omeprazole and lansoprazole, toward ivabradine was unlikely to occur, but this still needs to be tested for confirmation in vivo. The results are consistent with other studies, in which even in situations where the potential for drug interactions was high, these could not be confirmed in vivo.6,9,10,14

After single administration of ivabradine alone, exposure data for S16257 [GenBank] and S18982 were in accordance with those previously obtained in healthy volunteers.15 After treatment with omeprazole or lansoprazole, the pharmacokinetics of ivabradine in healthy subjects were not altered either. It could be concluded that no metabolic interaction was noted for either ivabradine or its main active metabolite (S18982). In addition, the change in gastric pH as consequence of the inhibition of gastric acid secretion seemed to exert no influence on ivabradine absorption.

The pharmacokinetic results, together with the activity and safety results, indicate that it is unlikely that the efficacy of ivabradine would be affected by coadministration with omeprazole or lansoprazole. Had a pharmacokinetic interaction been evidenced, a pharmacodynamic interaction study with patients might have been interesting.

As expected, the treatments were well tolerated. No safety concerns regarding adverse events, blood pressure, and laboratory or ECG parameters arose during the study.

In conclusion, analysis of ivabradine and its main active metabolite (S18982) plasma concentrations in healthy volunteers previously treated with omeprazole or lansoprazole for 5 days did not reveal any pharmacokinetic or pharmacodynamic interaction with omeprazole or lansoprazole toward ivabradine.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We thank all the medical, nursing, and administrative personnel of the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos, for their enthusiastic cooperation and their dedication to this project. This study was financed by Laboratorios Servier, through a contract managed by Universidad Complutense de Madrid.

DOI: 10.1177/0091270006291624


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Vilaine JP, Thollon C, Villeneuve N. Procoralan, a new selective I(f) current inhibitor. Eur Heart J. 2003;5(Suppl G): G26-G35.

2. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64: 1757-1765.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Tardif JC, Ford I, Tendenra M, Fox K. Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine versus atenolol in stable angina: a 4-month randomised, double-blind, multicenter trial [abstract]. Eur Heart J. 2003;24(Suppl): 20.

4. Borer JS, Fox KP, Lerebours G. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107: 817-823.[Abstract/Free Full Text]

5. Procorolan [summary of product characteristics]. Neuilly sur Seine, France: Les laboratoires Servier; 2005.

6. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Clin Pharmacokinet. 1996;31: 9-28.[Medline] [Order article via Infotrieve]

7. 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][Web of Science][Medline] [Order article via Infotrieve]

8. Meyer A. Metabolic interaction of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs. Eur J Gastroenterol Hepatol. 1996;8(Suppl 1): S21-S25.[Medline] [Order article via Infotrieve]

9. Klippert P, Jeanniot JP, Polve S, Lefevre C, Merdjan H. Determination of ivabradine and its N-demethylated metabolite in human plasma and urine and in rat and dog plasma by a validated high-performance liquid chromatographic method with fluorescence detection. J Chromatogr Biomed Appl. 1998;719: 125-133.[CrossRef]

10. Lefebvre RA, Flouvat B, Karolac-Tamisier S, Moerman E, Van Ganse E. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther. 1992;52: 458-463.[Web of Science][Medline] [Order article via Infotrieve]

11. Cavanaughs JH, Karol MD. Lack of pharmacokinetic interaction after administration of lansoprazole or omeprazole with prednisone. J Clin Pharmacol. 1996;36: 1064-1071.[Free Full Text]

12. Dammann HG. Therapy with omeprazole and clarithromycin increases serum carbamazepine levels in patients with H. pylori gastritis. Dig Dis Sci. 1996;41: 519-520.[Web of Science][Medline] [Order article via Infotrieve]

13. Christians U, Schmidt G, Bader A, et al. Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol. 1996;41: 187-190.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Gerson LB, Triadafilopoulos G. Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol. 2001;13: 611-616.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Ragueneau I, Laveille C, Jochemsen R, Weber C, Funck-Brentano C, Jaillon P. Pharmacokinetic-pharmacodynamic modelling of the effects of S16257, a direct sinus node modulator, on heart rate in healthy volunteers. Clin Pharmacol Ther. 1998;64: 192-203.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Portolés, A.
Right arrow Articles by Moreno, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Portolés, A.
Right arrow Articles by Moreno, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS