| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
DRUG INTERACTIONS |
From AstraZeneca, Wilmington, Delaware (Dr Simonson, Mr Mitchell, Dr Schneck); AstraZeneca, Alderley Park, Cheshire, UK (Dr Martin); Clinical Pharmacology Associates, Miami, Florida (Dr Lasseter); and Clinical Study Centers, LLC, Little Rock, Arkansas (Dr Gibson).
Address for reprints: Dennis W. Schneck, AstraZeneca, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437.
 |
ABSTRACT |
|---|
 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: Rosuvastatin • warfarin • pharmacokinetics • drug interaction
The S-warfarin enantiomer is 5 times more potent as a vitamin K antagonist then R-warfarin, and the CYP2C9 isoenzyme is responsible for 80% to 85% of its metabolism.14 Warfarin drug-drug interaction trials with rosuvastatin were performed because of the reported warfarin interactions with other HMG-CoA reductase inhibitors and because CYP2C9 is a common enzyme involved with rosuvastatin and S-warfarin metabolism. An initial trial (trial A) was performed in healthy volunteers given both drugs. A subsequent trial (trial B) assessed the effect of rosuvastatin on the INR response to warfarin in patients receiving stable warfarin therapy. The results from both trials are presented in this article.
|
SUBJECTS AND METHODS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
Trial A consisted of two 14-day treatment periods (periods 1 and 2). During period 1, volunteers were administered oral doses of rosuvastatin (Crestor, licensed by AstraZeneca from Shionogi and Co Ltd, Japan), 40 mg or placebo on demand (o.d.), for 10 days (at approximately 0700 hours on days 1-10); a single dose of warfarin 25 mg was coadministered with rosuvastatin or placebo on day 7. During period 2, volunteers were crossed over to whichever treatment they did not receive in period 1. The sequence of the rosuvastatin/placebo treatments was determined by a randomization scheme prepared by the AstraZeneca Biostatistics Group. Periods 1 and 2 were separated by 17 days; there were 31 days between the doses of warfarin. Volunteers remained in the research center for both 14-day treatment periods.
Trial B consisted of two 14-day treatment periods (periods 1 and 2). During period 1, patients being treated with warfarin took their daily dose of warfarin with rosuvastatin 10 mg for up to 14 days (approximately 3 hours after their evening meal on days 1-14). Patients who completed period 1 could enter period 2 provided their mean INR during the 10-mg period was 
3 and had not increased more than 40% from the baseline value. During period 2, patients took their daily dose of warfarin with rosuvastatin 80 mg for up to 14 days. Daily INR measurements were obtained from each patient during each treatment period. Patients with an INR >4 at any time after the initiation of rosuvastatin treatment were withdrawn from the trial.
Trial Populations
Trial A participants were healthy volunteers aged between 18 and 65 years identified from their medical history, physical examination, or electrocardiogram (ECG). In addition, prothrombin time (PT), activated partial thromboplastin time (aPTT), total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and creatine kinase had to be within the normal reference ranges. Sixteen men and 2 women entered this trial. Their mean age, height, and weight were 41.1 years (range, 27-54 years), 171.5 cm (range, 157.5-188.0 cm), and 75.2 kg (range, 60.9-94.5 kg), respectively.
Trial B participants were between 18 and 75 years old and were on chronic warfarin therapy. Warfarin indications included chronic atrial fibrillation (n = 4), previous stroke (n = 1), prevention of venous thrombosis (n = 1), and mechanical heart valve (n = 1). Patients were on a stable warfarin regimen for at least 1 month before trial screening and had a mean baseline INR value between 2 and 3 (determined from the mean of 3 values assessed during the screening period, with all values within 30% of the highest value). Five men and 2 women entered this trial. Their mean age, height, and weight were 57 years (range, 42-71 years), 177 cm (range, 147-185 cm), and 90 kg (range, 55-124 kg), respectively.
Pharmacodynamic Evaluation (Trials A and B)
Blood samples (5 mL of venous blood) for the determination of PT were collected during screening and on day 7 (before and 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, and 168 hours after coadministration of warfarin and rosuvastatin/placebo) of both treatment periods in trial A and during screening and on days 1 to 14 of both treatment periods in trial B (and also following completion/withdrawal).
Samples were analyzed by accredited local laboratories (trial A: Quest Diagnostics, Inc, Miami, Fla; trial B: Baptist Health Laboratory, Little Rock, Ark). The thromboplastin reagent used by these laboratories was Innovin by Dade, which had an International Sensitivity Index (ISI) of 0.98. Prothrombin times determined by thromboplastin addition were measured on an Electra 1600 coagulometer and reported in the INR system. The INR, which was calculated as the ratio of subject PT (seconds)/mean of normal PT (seconds) raised to the ISI, was the primary measure in these trials.
The INR parameters determined in trial A included area under the INR-time curve from time 0 to the time of the last quantifiable measurement (AU-INR0-t), maximum INR (maxINR), and the time at which maxINR was observed (tmaxINR). The AU-INR0-t was determined using the linear trapezoidal rule, and maxINR and tmaxINR were determined by visual inspection of the INR-time curves. Daily INR values were determined in trial B.
Pharmacokinetic Evaluation (Trial A Only)
During periods 1 and 2, blood samples (5 mL of venous blood) for R- and S-warfarin assay were collected on day 7 (before and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, 96, 120, 144, and 168 hours after coadministration of warfarin and rosuvastatin/placebo). Blood was collected into tubes containing lithium-heparin anticoagulant and centrifuged within 30 minutes. The resultant plasma sample was maintained at –20°C or colder until assay.
During periods 1 and 2, blood samples (5 mL of venous blood) for rosuvastatin assay were collected on day 6 (before and 1, 3, 5, 8, 12, and 24 hours after administration of rosuvastatin/placebo) and day 7 (1, 3, 5, 8, 12, 24, 48, 72, and 96 hours after coadministration of warfarin and rosuvastatin/placebo). Blood was collected into tubes containing lithium-heparin anticoagulant and centrifuged within 30 minutes. The resultant plasma sample was mixed 1:1 with acetate buffer (0.1 M, pH 4.0) and stored at –70°C until assay.
Plasma samples were analyzed for R- and S-warfarin at BAS Analytics Ltd (Kenilworth, UK) using automated sequential trace enrichment of dialysates followed by chiral chromatography with ultraviolet detection. Extraction began by protein precipitation using acetonitrile. Following centrifugation, the supernatant was fed into an ASTED online trace enrichment dialyzer. The dialysate was fed onto a high-performance liquid chromatography (HPLC) column using a 91:4:5 water/phosphate buffer 500-mM/L pH 7/ethanol mobile phase, a 150 x 4.6-mm, 5-µm Ultron ES-OVM chiral column (Hichrom). R- and S-warfarin were detected on a UV detector at a wavelength of 307 nm. Calibration (range, 10-2500 ng/mL) and OC samples were spiked with R- and S-warfarin. The addition of rosuvastatin to the samples did not interfere with warfarin determination. An internal standard was not employed in this assay. The limit of quantitation for R- and S-warfarin was 10 ng/mL, and the method has been shown to be linear up to concentrations of 2500 ng/mL. Mean imprecision and inaccuracy values for R-warfarin quality control (QC) samples (at all concentrations) were <8% and <9%, respectively. Mean imprecision and inaccuracy values for S-warfarin QC samples (at all concentrations) were <5% and <9%, respectively.
Plasma samples were analyzed for rosuvastatin at Quintiles Scotland Ltd (Edinburgh, UK) using HPLC with tandem mass-spectrometric detection (LC/MS/MS); this method has been described elsewhere.15,16 The effective limit of quantitation for rosuvastatin was 0.2 ng/mL. The LC/MS/MS assay for rosuvastatin is highly specific, and the warfarin enantiomers do not interfere with rosuvastatin plasma measurements. Correlation coefficients for rosuvastatin calibration curves were 0.997 to 1.00. Mean imprecision and inaccuracy values for QC samples (at all concentrations) were <8% and <6%, respectively.
R- and S-warfarin pharmacokinetic parameters determined included area under the plasma concentration-time curve from time 0 to infinity (AUC), maximum observed plasma drug concentration (Cmax), time at which Cmax was observed (tmax), and terminal elimination half-life (t1/2). Rosuvastatin pharmacokinetic parameters determined included minimum observed plasma drug concentration (Cmin) (for assessment of time to steady state), area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24), Cmax, and tmax.
AUC was determined using the linear trapezoidal rule up to the last quantifiable concentration and thereafter by extrapolation by linear regression of the terminal phase. AUC0-24 was determined using the linear trapezoidal rule. Cmax, tmax, and Cmin were determined by visual inspection of the plasma concentration-time curves. t1/2 was determined by log-linear regression of the terminal portion of the concentration-time profiles when there were sufficient data.
Statistical Methods
The sample size required to show a clinically meaningful difference between the treatment groups in trial A was calculated based on warfarin literature.17 Asample size of 12 would have had 90% power to detect a 10% difference between rosuvastatin and placebo in AUC and Cmax for R- and S-warfarin and AU-INR0-t. Twenty volunteers were recruited to ensure that 12 completed the trial.
For the analysis of INR parameters in trial A, paired t tests were performed comparing within-subject ratios (rosuvastatin/placebo) in AU-INR0-t and maxINR. The data were log-transformed before performing the hypothesis test.
For the analysis of warfarin pharmacokinetic parameters in trial A, paired t tests were performed comparing the within-subject treatment ratios (rosuvastatin/placebo) in R- and S-warfarin AUC and Cmax. AUC and Cmax data were log-transformed before performing the hypothesis test. Analysis of t1/2 was performed using a paired t test without transformation.
For the analysis of warfarin pharmacokinetic parameters in trial A, 90% confidence intervals (CIs) for the rosuvastatin/placebo ratios were constructed based on the least squares means from the analysis of variance (ANOVA) of log-transformed AUC and Cmax values and linear-scale t1/2 values (effects for sequence, volunteer within sequence, treatment, and period were fitted).
For the analysis of rosuvastatin pharmacokinetic parameters in trial A, 90% CIs for the before/after warfarin (ie, day 6/day 7) ratios were constructed based on the least squares means from the ANOVA of log-transformed AUC0-24 and Cmax values (effects for sequence, volunteer within sequence, before/after warfarin state, and period were fitted).
It was planned to recruit 14 patients into trial B, but recruitment was stopped after 7 patients had enrolled. The planned analysis was therefore simplified to analyze the INR data using descriptive statistics and individual graphs of INR data over time.
Tolerability
Throughout both trials, adverse event reports and clinical laboratory data (including hematology and urinalysis parameters, hepatic biochemistry, renal biochemistry, and creatine kinase) were collected. Vital signs (blood pressure and pulse rate) were measured, and ECGs and physical examinations were performed.
|
RESULTS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
1.2) by 168 hours after warfarin administration.
|
|
In trial B, 2 out of 7 patients developed an INR >4 during the rosuvastatin 10-mg period, and 4 out of 5 patients whose INR values were <3 during the rosuvastatin 10-mg dosing period developed an INR >4 during the rosuvastatin 80-mg period, resulting in 6 of the 7 patients withdrawing from the trial (Figure 2). The baseline, maximum, and end-of-treatment period INR values are listed in Table II. No patient experienced a significant bleeding episode, and all INR values returned to within the therapeutic range (
2 and 3) 2 to 5 days after discontinuing rosuvastatin and warfarin.
|
|
Pharmacokinetics: R- and S-Warfarin (Trial A Only)
R- and S-warfarin mean plasma concentrations over time for the rosuvastatin and placebo groups are presented in Figure 3. Mean AUC and Cmax values for the warfarin enantiomers were similar during the rosuvastatin and placebo treatment periods (Table III). The treatment effects (mean ratios of AUC and Cmax rosuvastatin + warfarin/placebo + warfarin) for these parameters were close to unity. R- and S-warfarin median tmax and mean t1/2 values were similar during the rosuvastatin and placebo treatment periods (Table III).
|
|
Pharmacokinetics: Rosuvastatin (Trial A Only)
Rosuvastatin Cmin values indicate that the compound had reached steady state after 6 days of dosing (gmean [coefficient of variation, %] values on days 6, 7, 8, 9, 10, and 11 were 2.12 [43.4], 1.98 [87.5], 2.53 [55.5], 1.83 [58.0], 1.62 [79.1], and 1.98 [50.5] ng/mL, respectively). Therefore, warfarin was coadministered when rosuvastatin was at steady state.
Administration of the single dose of warfarin did not affect rosuvastatin systemic exposure. Rosuvastatin gmean AUC0-24 values of 182 and 195 ng·h/mL were obtained before and after warfarin dosing, respectively. The treatment effect (before/after ratio of geometric least squares means) for this parameter was 0.93, with a 90% CI of 0.86 to 1.02. The gmean Cmax values were also similar before and after warfarin dosing: 20.5 and 19.7 ng/mL, respectively (treatment effect 1.04; 90% CI 0.92-1.18). Peak rosuvastatin plasma concentrations were observed 1 to 5 hours postdose in the presence (median 5.0 hours) and absence (median 4.0 hours) of warfarin. Rosuvastatin systemic exposure in this trial was typical of that seen in other volunteer trials.18-21
Tolerability
In trial A, there were no serious adverse events and no clinically relevant changes in vital signs or medical examinations. One volunteer had an alanine aminotransferase increase >3 times the upper limit of normal (152 U/L) after administration of rosuvastatin and warfarin (period 2) that was reported as an adverse event. The increase was first detected 7 days after beginning rosuvastatin treatment; it was greatest 7 days later (4 days after stopping rosuvastatin and 7 days after the warfarin dose) and normal 5 days after that. The volunteer completed the trial and had no symptoms. There were no other clinically relevant changes in clinical laboratory parameters (other than the changes in INR described above). Four volunteers were reported to have nonserious adverse events that the investigator considered possibly related to trial treatment. The most frequently occurring events were headache, increased cough, and pruritus.
In trial B, although 6 of the 7 patients developed an INR >4, no significant bleeding events occurred, and few other adverse experiences were identified.
|
DISCUSSION |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
In trial B, 2 out of 7 patients receiving chronic warfarin therapy (stable baseline INR values between 2 and 3) who were administered daily doses of rosuvastatin 10 mg developed an INR >4. Four of the 5 patients who were subsequently administered daily doses of rosuvastatin 80 mg developed an INR >4. The more frequent occurrence of INR values >4 during dosing with rosuvastatin 80 mg suggests a dose-response relationship for this interaction. The 80-mg dose of rosuvastatin is not approved for clinical use; it was used in trial B to explore possible dose-response effects on INR. The INR values >4 were observed on days 4 to 14 of each treatment period, and the values returned to within the therapeutic range 2 to 5 days after discontinuation of rosuvastatin and warfarin.
The results of trials A and B indicate that rosuvastatin can enhance the anticoagulant effect of warfarin. Rosuvastatin did not affect the total plasma concentrations of either the S- or R-enantiomer of warfarin. However, these measurements do not exclude a pharmacokinetic interaction as a mechanism for the interaction observed. It is possible that rosuvastatin might reduce the clearance of unbound S- or R-warfarin. This would result in a higher unbound and total plasma concentrations of these enantiomers because the free plasma concentration of these enantiomers is dependent on their clearance from plasma.23,24
Both rosuvastatin and warfarin are bound to plasma proteins—chiefly albumin (88% and 99%, respectively) (data on file, AstraZeneca, Alderley Park, Cheshire, UK). Displacement of warfarin protein binding by rosuvastatin would result in a reduction in total warfarin plasma concentrations. These 2 separate effects would lead to minimal change in total warfarin plasma concentrations but an increased unbound warfarin plasma concentration, which could lead to a greater effect on INR. It is of interest to note that rosuvastatin mean Cmax in trial A was approximately 20 ng/mL, which is well below the plasma concentration of albumin (approximately 0.7 mM)25 and the Cmax of both the R- and S-warfarin enantiomers. This observation suggests that displacement of warfarin enantiomers from plasma albumin is unlikely to occur at these rosuvastatin plasma concentrations.26 In vitro studies with human hepatic microsomes have shown that rosuvastatin produced only a 10% inhibition of CYP2C9 activity at a concentration of 50 µM and less than this degree of inhibition on CYP3A4 activity.2 Only slow metabolism of rosuvastatin (5%-50% over 3 days) of rosuvastatin was observed with cultures of human hepatocytes.2 CYP2C9 was the principal isoenzyme responsible for this slow metabolism. Less than 10% of a 14C dose of rosuvastatin was recovered as N-desmethyl rosuvastatin, the metabolite formed during CYP2C9 oxidation of rosuvastatin.27 Fluconazole (a potent inhibitor of CYP2C9) had no significant effect on rosuvastatin plasma exposure in humans.28 These observations suggest that inhibition of either the S- or R-enantiomers of warfarin is unlikely to be the mechanism of the interaction observed.
Warfarin produces its anticoagulant effect by inhibiting the reductase enzyme(s) in the vitamin K cycle, thus reducing regeneration of the active form of the vitamin. It is not known if rosuvastatin or other statins have an effect on the vitamin K cycle. Recently, simvastatin has been shown to increase the INR response to warfarin in 29 patients on stable warfarin therapy (mean baseline INR value 2.5; mean INR value with simvastatin 3.2).5 Cases of excessive warfarin anticoagulation have also been reported for lovastatin,8-10 pravastatin,11 and fluvastatin.12,13 Thus, other members of the HMG-CoA reductase inhibitor class can enhance the anticoagulant activity of warfarin. The mechanism for these interactions is also unknown.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
|---|
1. Schuster H. Rosuvastatin—a highly effective new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor: review of clinical trial data at 10-40 mg doses in dyslipidemic patients. Cardiology. 2003;99: 126-139.[CrossRef][Medline] [Order article via Infotrieve]
2. McCormick AD, McKillop D, Butters CJ, Miles GS, Baba T, Touchi A, Yamaguchi Y. ZD4522—an HMG-CoA reductase inhibitor free of metabolically mediated drug interactions: metabolic studies in human in vitro systems [abstract 46]. J Clin Pharmacol. 2000;40: 1055.
3. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest. 2001;119: 22S-38S.
4. Levine MN, Rascob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119: 108S-121S.
5. Kamali F. The effect of simvastatin co-medication on warfarin anticoagulation response and dose requirements. Thromb Haemost. 2003;89: 949-950.[Medline] [Order article via Infotrieve]
6. Gaw A, Wosornu D. Simvastatin during warfarin therapy in hyperlipoproteinaemia. Lancet. 1992;340: 979-980.[Web of Science][Medline] [Order article via Infotrieve]
7. Lin JC, Ito MK, Stolley SN, Morreale AP, Marcus DB. The effect of converting from pravastatin to simvastatin on the pharmacodynamics of warfarin. J Clin Pharmacol. 1999;39: 86-90.[Abstract]
8. Iliadis EA, Konwinski MR. Lovastatin during warfarin therapy resulting in bleeding. Pa Med. 1995;98: 31.[Medline] [Order article via Infotrieve]
9. Hoffman HS. The interaction of lovastatin and warfarin. Conn Med. 1992;56: 107.
10. Ahmad S. Lovastatin: warfarin interaction. Arch Intern Med. 1990;150: 2407.
11. Trenque T, Choisy H, Germain M-L. Pravastatin: interaction with oral anticoagulant? Br Med J. 1996;312: 886.
12. Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction. Ann Pharmacother. 1997;31: 790.[Medline] [Order article via Infotrieve]
13. Trilli LE, Kelley CL, Aspinall SL, Kroner BA. Potential interaction between warfarin and fluvastatin. Ann Pharmacother. 1996;30: 1399-1402.[Abstract]
14. Redman AR. Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy. 2001;21: 235-242.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Hull CK, Penman AD, Smith CK, Martin PD. Quantification of rosuvastatin in human plasma by automated solid-phase extraction using tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;772: 219-228.[Medline] [Order article via Infotrieve]
16. Martin PD, Kemp J, Dane AL, Warwick MJ, Schneck DW. No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol. 2002;42: 1352-1357.[Abstract]
17. Kong AT, Tomasko L, Waldman SA, et al. Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol. 1995;35: 1008-1015.[Abstract]
18. Martin PD Warwick MJ, Dane AL, Cantarini MV. A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. Clin Ther. 2003;25: 2215-2224.[CrossRef][Medline] [Order article via Infotrieve]
19. Martin PD, Warwick MJ, Dane AL, Brindley C, Short T. Absolute oral bioavailability of rosuvastatin. Clin Ther. 2003;25: 2553-2563.[CrossRef][Medline] [Order article via Infotrieve]
20. Warwick MJ, Dane AL, Raza A, Schneck DW. Single- and multiple-dose pharmacokinetics and safety of the new HMG-CoA reductase inhibitor ZD4522 [abstract MoP19:W6]. Atherosclerosis. 2000;151: 39.
21. Martin PD, Dane AL, Nwose OM, Schneck DW, Warwick MJ. No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor. J Clin Pharmacol. 2002;42: 1116-1121.[Abstract]
22. Duursema L, Müller FO, Hundt HKL, Heyns A du P, Meyer BH, Luus HG. Model to detect warfarin-drug interactions in man. Drug Invest. 1992;4: 395-402.
23. Greenbblatt DJ, Sellers EM, Koch-weser J. Importance of protein binding for the interpretation of serum or plasma drug concentrations. J Clin Pharmacol. 1982;22: 259-263.[Abstract]
24. Gugler R, Shoeman DW, Huffman DH, Cohlmia JB, Azarnoff DL. Pharmacokinetics of drugs in patients with the nephrotic syndrome. J Clin Invest. 1975;55: 1182-1189.
25. Kock-weser J, Sellars EM. Binding of drugs to serum albumin. N Engl J Med. 1976;294: 311-316.[Web of Science][Medline] [Order article via Infotrieve]
26. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications. 2nd ed. Philadelphia: Lea & Febiger; 1989.
27. Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25: 2822-2835.[CrossRef][Medline] [Order article via Infotrieve]
28. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2002;58: 527-531.[CrossRef][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 |
