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
Right arrow Citation Map
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 HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scott, G.
Right arrow Articles by Rordorf, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scott, G.
Right arrow Articles by Rordorf, C.
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?
Journal of Clinical Pharmacology, 2004; 44:193-199
© 2004 the American College of Clinical Pharmacology

DRUG INTERACTIONS

Lumiracoxib: Pharmacokinetic and Pharmacodynamic Profile When Coadministered with Fluconazole in Healthy Subjects

Graham Scott, PhD, Linda Yih, BSc, Ching-Ming Yeh, PhD, Slavica Milosavljev, MS, Aziz Laurent, MD and Christiane Rordorf, MD

From the Department of Exploratory Clinical Development, Novartis Pharmaceuticals, Horsham, United Kingdom (Dr. Scott); Departments of Exploratory Clinical Development, Biostatistics, and Bioanalytics, Novartis Pharmaceuticals, East Hanover, New Jersey (L. Yih, Dr. Yeh, S. Milosavljev); PPD Development, Austin, Texas (Dr. Laurent); and Department of Exploratory Clinical Development, Novartis Pharmaceuticals, Basel, Switzerland (Dr. Rordorf).

Address for reprints: Christiane Rordorf, MD, Department of Exploratory Clinical Development, Novartis Pharma AG, WSJ 210-313, CH-4002, Basel, Switzerland.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This two-way crossover study evaluated the effect of fluconazole on the pharmacokinetics and selective COX-2 inhibition of lumiracoxib. Thirteen healthy subjects were randomized to fluconazole (day 1: 400 mg; days 2-4: 200 mg) or no drug. On day 4, all subjects received a single dose of lumiracoxib (400 mg). Lumiracoxib pharmacokinetics were assessed during the following 48 hours. Thromboxane B2 (TxB2) inhibition was measured prior to lumiracoxib dosing and 2 hours afterwards. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC0-{infty} but had no effect on lumiracoxib mean Cmax. The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC0-{infty} was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for Cmax was 1.11 (90% CI = 0.98, 1.27). The decrease in TxB2 from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB2 decrease was seen. As fluconazole is a strong inhibitor of cytochrome P450 (CYP) 2C9, other CYP2C9 inhibitors are unlikely to affect lumiracoxib pharmacokinetics with clinical relevance, making dosage adjustment unnecessary.

Key Words: Lumiracoxib • fluconazole • drug interactions • COX-2 inhibitors • pharmacokinetics

Lumiracoxib is a novel member of the cyclooxygenase-2 (COX-2) selective inhibitor family of anti-inflammatory agents.1 Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and COX-2, leading not only to their beneficial therapeutic effects but also to a number of detrimental effects, including their most limiting toxicity, which is gastrointestinal.1-3 Side effects such as dyspepsia and gastroduodenal ulceration, as well as life-threatening complications such as gastrointestinal perforation and hemorrhage, are thought to be related to the inhibition of the cytoprotective COX-1 isoform. These can seriously limit the long-term therapeutic use of NSAIDs.3 Indeed, COX-2-selective inhibitors tested in controlled clinical trials thus far appear to be associated with fewer gastrointestinal side effects when compared to NSAIDs.4-8 Lumiracoxib has been shown to be a COX-2-selective inhibitor with rapid absorption and a relatively short half-life.9,10 Lumiracoxib has proven to be as effective as conventional NSAIDs in relieving pain in osteoarthritis11,12 and has demonstrated a significantly improved gastrointestinal tolerability and safety profile in comparison to traditional NSAIDs in both healthy subjects and patients with osteoarthritis.13-15

Lumiracoxib is metabolized in humans largely by the cytochrome P450 CYP2C9 isoform (data on file at Novartis). Fluconazole is known to interact with drugs whose clearance is dominated by CYP2C9 and CYP3A4.16-24 In most cases, inhibition of CYP2C9 by fluconazole leads to increased active drug concentrations and increased pharmacodynamic action, sometimes resulting in greater toxicity of the interacting drug.16-19,21-24 Fluconazole, on the other hand, can inhibit the metabolism of an inactive parent drug to an active metabolite, so reducing any therapeutic benefit (e.g., the interaction between fluconazole and losartan).20 If any interaction were to occur between fluconazole and lumiracoxib, it might be expected to lead to increased lumiracoxib plasma concentrations and, depending on the degree of the increase, potentially to a loss of COX-2-selective inhibition (i.e., inhibition of COX-1). Such an effect might detract from the safety profile of lumiracoxib, leading to greater gastrointestinal toxicity. Therefore, it was considered important to assess the possible interaction between fluconazole and lumiracoxib. The purpose of this study was to evaluate the possible effects of multiple oral doses of fluconazole on the pharmacokinetics (PK) of a single oral dose of lumiracoxib and on its selective inhibition of COX-2.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Healthy male and female subjects ages 18 to 65 who weighed between -20% and +20% of normal body weight for their height and frame size were eligible for participation in the study. Female subjects had to be at least 2 years postmenopausal, surgically sterilized at least 6 months prior to starting the study, or using a double-barrier method of local contraception. Lactating female subjects were excluded from the study. Subjects were also excluded from study participation if they smoked (as evidenced by urine cotinine levels > 500 ng/mL), tested positive for hepatitis B or C or for HIV, had a history of alcohol abuse within 12 months prior to starting the study, or had a platelet count less than 100,000/µL or a polymorphonuclear cell count less than 1500/µL. All prescription and over-the-counter drugs (except acetaminophen) were to be discontinued at least 2 weeks prior to the study initiation. Any inducer or inhibitor of CYP2C9, including but not limited to rifampin, fluconazole, ketoconazole, itraconazole, metronidazole, ritonavir, and any antiepileptic drugs, must have been discontinued at least 2 months prior to dosing. Subjects were also screened for CYP2C9 genotype polymorphism to facilitate the interpretation of results. All subjects provided written informed consent prior to study participation. Study approval was given by the PPD Development Institutional Review Board, and the investigation was carried out in accordance with the principles of the Declaration of Helsinki, as revised in 1996.25

Study Design
The study was conducted in a randomized, open-label, two-period crossover design. Subjects who met study eligibility criteria were enrolled at a screening visit within 21 days prior to starting the study. After screening, the subjects were randomized to a treatment sequence and administered either fluconazole for 4 days (400 mg on day 1 and 200 mg on days 2-4) or no drug for 4 days. On day 4, they all received a single 400-mg oral dose of lumiracoxib. After a washout period of 14 days (for those who received no fluconazole during the first treatment period) or 17 days (for those who received fluconazole during the first treatment period), the subjects received the alternate treatment. On days 4 to 6 of each treatment period, a 48-hour lumiracoxib PK profile was assessed. On day 4, serum TxB2 concentrations were assessed at hour 0 and at 2 hours postdose; serum TxB2 is used as an indicator of platelet COX-1 activity since TxB2 is formed from COX-1-derived TxA2 production.1,26 Subjects were confined to the study center from at least 10 hours prior to lumiracoxib administration on day 4 of each treatment period until the final PK sample was obtained.

No concomitant medications except those required to treat adverse events were allowed from screening until study completion. No alcohol could be consumed within 72 hours prior to the first dose of study medication until after study completion. The intake of xanthine-containing food or beverages (e.g., coffee, tea, chocolate) was to be discontinued 12 hours prior to lumiracoxib dosing and not resumed until after leaving the center. All subjects underwent an overnight fast of at least 10 hours prior to taking lumiracoxib.

Pharmacokinetic Assessments
Blood samples were obtained predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours after the lumiracoxib dose each treatment period. Plasma lumiracoxib concentrations were measured by means of a validated high-pressure liquid chromatography/mass spectrometry assay with a limit of quantitation of 10 ng/mL. Between-run coefficients of variation were <= 12.2% for lumiracoxib, and analytical recoveries ranged from 96.3% to 105%.

Pharmacodynamic Assessments
Blood samples for measurement of serum TxB2 were obtained at hour 0 and 2 hours after the lumiracoxib dose each treatment period. Blood samples (2 mL) were collected by venipuncture into regular glass Vacutainers containing no anticoagulants. Within 5 minutes after blood collection, the Vacutainers were incubated for 1 hour at 37°C to allow the blood to clot. Serum was collected, immediately centrifuged, and stored at -70°C until assayed for TxB2. Serum TxB2 concentrations were determined by PPD Development, Inc. using a TxB2 ELISA kit. The limit of assay sensitivity was 100 pg/mL.

Safety Assessments
Safety and tolerability of the study drugs and procedures were monitored by means of complete physical examinations, measurement of vital signs, serum and urine chemistry, hematology, and recording of adverse events, concomitant medications, and electrocardiograms.

Study Drugs
Lumiracoxib 200-mg tablets were supplied by Novartis Pharmaceuticals. The dose of 400 mg lumiracoxib once daily was chosen because it is the highest dose anticipated for clinical use. Commercially available Diflucan® (fluconazole; 200 mg tablets, all from the same lot) was purchased by the study site. Although steady-state concentrations of fluconazole are typically reached within 5 to 10 days of once-daily doses of 50 to 400 mg, the administration of a loading dose (twice the usual maintenance dose) produces plasma concentrations that approximate steady state by the second day.24

Statistical Analyses
Twelve subjects were required to complete the study. This sample size was chosen based in part on the results of a previous lumiracoxib PK study, in which a coefficient of variation (CV) of 25% was observed for the area under the curve (AUC) parameter. Assuming a greater than 50% difference in the mean AUCs between lumiracoxib alone and lumiracoxib plus fluconazole to be clinically important, in addition to using a power of 80% with a significance level of 5%, a total of 12 subjects would be adequate to show whether a significant difference had occurred.

Standard noncompartmental PK parameters were derived from plasma concentration profiles. Arithmetic means and standard deviations (SD) for the AUC0-{infty} and Cmax of lumiracoxib were calculated. An analysis of variance (ANOVA) was used to compare treatment effects. Log-transformed AUC0-{infty} and Cmax were used for the assessment of any difference between the fluconazole-treated and the non-fluconazole-treated groups. The model for analysis included sequence, treatment, and period as fixed factors and subject (sequence) as a random factor. Ninety-percent confidence intervals (CIs) were calculated for both the AUC0-{infty} and Cmax from the ratio of the lumiracoxib coadministered drug to lumiracoxib taken alone.

A similar analysis of variance was performed on the change from baseline in TxB2 to test for any difference between coadministration of lumiracoxib with fluconazole and lumiracoxib alone.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
A total of 32 subjects were screened for eligibility to participate in the study; of these, 13 subjects were enrolled in and completed the study. Nine screened subjects were ineligible for study participation, 5 chose not to participate, and 5 were eligible for study participation on a backup basis. The demographic characteristics of the 13 subjects who entered and completed the study are provided in Table I. The subjects were predominantly female and Caucasian. The following CYP2C9 genotypes were observed: CYP2C9*1/*1 (8 subjects), CYP2C9*1/*2 (4 subjects), and CYP2C9*1/*3 (1 subject).


View this table:
[in this window]
[in a new window]
  		Table I Demographics and Background Characteristics

 

Pharmacokinetics
Coadministration of lumiracoxib with fluconazole did not alter the lumiracoxib plasma concentration versus time profile (Figure 1). Mean PK parameters for lumiracoxib alone and during coadministration with fluconazole are provided in Table II. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC0-{infty} but had no effect on lumiracoxib mean Cmax. The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC0-{infty} was 1.19 (90% CI = 1.12, 1.27) and for Cmax was 1.11 (90% CI = 0.98, 1.27). No obvious influence of CYP2C9 genotype on the plasma concentrations of lumiracoxib was observed.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Mean plasma lumiracoxib concentration versus time curves for a single oral 400-mg dose of lumiracoxib given alone () and on day 4 of treatment with fluconazole ({circ}; 400 mg fluconazole on day 1 and 200 mg on days 2-4; n = 13).

 

View this table:
[in this window]
[in a new window]
  		Table II Single-Dose Pharmacokinetics of Lumiracoxib Alone and on Day 4 of Fluconazole Administration

 

Pharmacodynamics
Figure 2 shows mean percent inhibition from baseline (±SD) of TxB2 generation at 2 hours postdose by lumiracoxib alone and lumiracoxib plus fluconazole. Lumiracoxib alone decreased mean TxB2 concentrations by 11.8% versus 7.1% for lumiracoxib plus fluconazole (Table III). The mean decrease from base-line in TxB2 was not significantly different between lumiracoxib given alone and with fluconazole (p = 0.74). No correlation was observed between plasma lumiracoxib concentrations and percent decrease in TxB2 (Figure 3).



View larger version (9K):
[in this window]
[in a new window]
  		Figure 2. Mean (±SD) percent inhibition of TxB2 generation from baseline by 400 mg lumiracoxib given alone (n = 13) or on day 4 of treatment with fluconazole (400 mg fluconazole on day 1 and 200 mg on days 2-4; N = 13).

 

View this table:
[in this window]
[in a new window]
  		Table III Effect of Lumiracoxib on TxB2 Generation When Given Alone or on Day 4 of Fluconazole Administration

 


View larger version (15K):
[in this window]
[in a new window]
  		Figure 3. Percentage inhibition of TxB2 generation from baseline at hour 2 versus lumiracoxib concentration at hour 2 for 400 mg lumiracoxib given alone (; n = 13) or on day 4 of treatment with fluconazole ({circ}; 400 mg fluconazole on day 1 and 200 mg on days 2-4; N = 13).

 

Safety
During this study, only one adverse event occurred, a headache in a subject after receiving lumiracoxib plus fluconazole. The event occurred 10 days after study drug administration and was not considered to be related to the study drug.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The aim of this study was to determine whether coadministration of fluconazole with lumiracoxib would affect its PK in healthy subjects and thus possibly lead to increased plasma lumiracoxib concentrations and a loss of COX-2 selectivity. Comparison of PK parameters indicated that there were no clinically relevant effects of steady-state administration of fluconazole on the single-dose PK of lumiracoxib. Fluconazole also had no effect on the potential for lumiracoxib to inhibit COX-1, as indicated by the similar decrease from baseline in TxB2 seen in both groups (TxB2 is an indicator of COX-1 inhibition—when COX-1 is inhibited, serum TxB2 concentrations decrease1,26). Whether given alone or with fluconazole, lumiracoxib did not inhibit COX-1 in any clinically relevant way. This observation supports the conclusion that fluconazole has no clinically relevant effect on the COX-2 selectivity of lumiracoxib. Given this and the lack of any clinically relevant effect of fluconazole on the lumiracoxib PK profile, no lumiracoxib dosage adjustment is considered to be necessary when it is coadministered with fluconazole. As fluconazole is considered to be a prototypical inhibitor of CYP2C9, other drugs that inhibit metabolism by this isozyme (e.g., fluvastatin,27 sulfaphenazole28) are also unlikely to affect the lumiracoxib PK profile in a clinically relevant manner; therefore, lumiracoxib dosage adjustment is also not considered to be necessary when it is coadministered with other inhibitors of CYP2C9.

The lack of relevant interaction between fluconazole and lumiracoxib differs from the significant interaction documented between fluconazole and celecoxib.27-30 Similar to lumiracoxib, celecoxib is metabolized primarily via CYP2C9. Concomitant administration of fluconazole at 200 mg once daily with celecoxib resulted in a twofold increase in plasma celecoxib concentrations as a consequence of fluconazole inhibition of CYP2C9.30 In contrast, the cytochrome P450 enzymes play a relatively minor part in the metabolism of rofecoxib,27 which is metabolized primarily via reduction by cytosolic enzymes.31

In conclusion, coadministration of a single 400-mg oral dose of lumiracoxib with fluconazole at steady state was not associated with any clinically meaningful alteration of the lumiracoxib PK profile or with any increase in COX-1 inhibition or corresponding loss of COX-2 selectivity in this study. Thus, no lumiracoxib dosage adjustment is considered necessary when it is coadministered with fluconazole or other inhibitors of CYP2C9.


   FOOTNOTES
 
DOI: 10.1177/0091270003262110

Submitted for publication August 12, 2003; Revised version accepted November 22, 2003.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

1. FitzGerald GA, Patrono C: The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345: 433-442.[Free Full Text]

2. Kulkarni SK, Jain NK, Singh A: Cyclooxygenase isoenzymes and newer therapeutic potential for selective COX-2 inhibitors. Methods Find Exp Clin Pharmacol 2000;22: 291-298.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR: Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999;96: 7563-7568.[Abstract/Free Full Text]

4. Goldstein JL, Agrawal NM, Silverstein F, Kaiser J, Burr AM, Verburg KM, et al: Celecoxib is associated with a significantly lower incidence of clinically significant upper gastrointestinal events in osteoarthritis and rheumatoid arthritis patients as compared to NSAIDs [abstract]. Gastroenterology 1999:116; G0758.

5. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjarnason T: COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 2000;47: 527-532.[Abstract/Free Full Text]

6. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282: 1921-1928.[Abstract/Free Full Text]

7. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, et al: Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282: 1929-1933.[Abstract/Free Full Text]

8. Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, et al: Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 2000;43: 370-377.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Marshall PJ, Berry JC, Wasvary J, Van Duzer J, Scott G, Rordorf C, et al: The in vitro and in vivo selectivity of COX189, a new and highly selective inhibitor of COX-2 [abstract SAT0013]. Ann Rheum Dis 2002;61(Suppl. 1): 259.

10. Scott G, Rordorf C, Blood P, Branson J, Milosavljev S, Greig G: Dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of COX189 in healthy subjects [abstract FRI300]. Ann Rheum Dis 2002;61(Suppl. 1); 242.[Abstract/Free Full Text]

11. Tannenbaum H, Berenbaum F, Reginster JY, Zacher J, Robinson J, Poor G, et al: Lumiracoxib (PrexigeTM) is effective in the treatment of osteoarthritis of the knee: a 13-week, placebo-controlled, active-comparator, double-blind study [abstract 487]. Arthritis Rheum 2002;46(Suppl. 9): S212.

12. Schnitzer TJ, Geusens P, Hasler P, Patel SK, Poor G, Senftleber I, Scott G: Efficacy and safety of COX189 in osteoarthritis: a multi-national study [abstract S336]. Arthritis Rheum 2000;43(Suppl. 9): 1616.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. Atherton C, Hayer R, Stevenson D, Jones JI, McKaig B, Cunliffe R, et al: No acute gastroduodenal erosive injury in a study of COX-189, a new highly selective COX-2 inhibitor [abstract M1730]. Gastroenterology 2002;122(4, Suppl. 1): A-344.

14. Rordorf C, Kellett N, Mair S, Ford M, Milosavljev S, Branson J, et al: Gastroduodenal tolerability of lumiracoxib vs. placebo and naproxen: a pilot endoscopic study in healthy male subjects. Aliment Pharmacol Ther 2003;18: 533-541.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Hawkey C: Reduced cumulative incidence of gastroduodenal ulcers with two doses of a new coxib, COX189, compared with standard therapeutic doses of ibuprofen in osteoarthritis patients [abstract WED-G-553]. Gut 2002;51(Suppl. 3): A313.[CrossRef]

16. Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, et al: Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996;24: 422-428.[Abstract]

17. Trapnell CB, Jamis-Dow C, Klecker RW, Collins JM: Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole. Antimicrob Agents Chemother 1997;41: 924-926.[Abstract]

18. Kunze KL, Wienkers LC, Thummel KE, Trager WF: Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies. Drug Metab Dispos 1996;24: 414-421.[Abstract]

19. Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ: Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000;56: 225-229.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Kaukonen KM, Olkkola KT, Neuvonen PJ: Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 1998;53: 445-449.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Kunze KL, Trager WF: Warfarin-fluconazole. III. A rational approach to management of a metabolically based drug interaction. Drug Metab Dispos 1996;24: 429-435.[Abstract]

22. Morita K, Konishi H, Shimakawa H: Fluconazole: a potent inhibitor of cytochrome P-450-dependent drug-metabolism in mice and humans in vivo. Comparative study with ketoconazole. Chem Pharm Bull (Tokyo) 1992;40: 1247-1251.[Medline] [Order article via Infotrieve]

23. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivisto KT: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001;69: 194-200.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

24. Pfizer, Inc.: Diflucan U.S. prescribing information, revised June 1998. Accessed May 30, 2003, from http://www.pfizer.com/download/uspi_diflucan.pdf

25. World Medical Association Declaration of Helsinki: Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277: 925-926.[Abstract/Free Full Text]

26. De Caterina R, Giannessi D, Bernini W, Gazzetti P, Michelassi C, L'Abbate A, et al: Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function. Eur Heart J 1985;6: 409-417.[Abstract/Free Full Text]

27. Garnett WR: Clinical implications of drug interactions with coxibs. Pharmacotherapy 2001;21: 1223-1232.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

28. Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD: Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. J Pharmacol Exp Ther 2000;293: 453-459.[Abstract/Free Full Text]

29. Davies NM, McLachlan AJ, Day RO, Williams KM: Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet 2000;38: 225-242.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

30. Pharmacia Corporation: Celebrex U.S. prescribing information, revised August 2002. Accessed May 30, 2003, from http://www.pfizer.com/download/uspi_celebrex.pdf

31. Merck & Co., Inc.: Vioxx U.S. prescribing information, issued April 2002. Accessed May 30, 2003, from http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf
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 has been cited by other articles:


Home page
 Pharmacol. Rev.Home page
S. J. Gardiner and E. J. Begg
Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice
Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
V.-V. Hynninen, K. T. Olkkola, K. Leino, S. Lundgren, P. J. Neuvonen, A. Rane, M. Valtonen, H. Vyyrylainen, and K. Laine
Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen.
Antimicrob. Agents Chemother., June 1, 2006; 50(6): 1967 - 1972.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. D. Rodrigues
IMPACT OF CYP2C9 GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?
Drug Metab. Dispos., November 1, 2005; 33(11): 1567 - 1575.
[Abstract] [Full Text] [PDF]

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
Right arrow Citation Map
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 HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scott, G.
Right arrow Articles by Rordorf, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scott, G.
Right arrow Articles by Rordorf, C.
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