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DRUG INTERACTIONS |
-Hydroxy Isomeric Metabolite
From the Departments of Clinical Pharmacokinetics (Dr Gustavson, Ms Schweitzer) and Clinical Pharmacology (Dr Achari, Mr Chira), the TriCor Global Project Team (Dr Yannicelli), Abbott Laboratories, Abbott Park, Illinois, and the Departments of Statistics (Mr Koehne-Voss) and Clinical Pharmacology (Dr Esslinger), Abbott Laboratories, Ludwigshafen, Germany.
Address for reprints: Linda E. Gustavson, PhD, Abbott Laboratories, Deptartment R4PK, Building AP13A, 100 Abbott Park Road, Abbott Park, IL 60064-6104.
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ABSTRACT |
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 TOP ABSTRACT STUDY DESIGN AND PROCEDURESRESULTSDISCUSSIONREFERENCES |
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-hydroxy-iso-pravastatin, were measured, and pharmacokinetics was assessed. Safety assessments were based on adverse events, physical examinations, electrocardiogram results, vital signs, and clinical laboratory testing. Safety results were unremarkable. Coadministration of fenofibrate had modest effects on pravastatin and 3-hydroxy-iso-pravastatin systemic exposures (AUC). Increases in pravastatin systemic exposures (19%-28%, on average) and 3-hydroxy-iso-pravastatin systemic exposures (24%-39%, on average) were observed upon coadministration, but individual changes were variable. Pravastatin and 3-hydroxy-iso-pravastatin systemic exposures were not statistically significantly different following the 1st and 10th doses of fenofibrate.
Key Words: Fenofibrate • 3-hydroxy-iso-pravastatin • pravastatin • pharmacokinetics • drug interactions
).2 Following oral administration, fenofibrate is well absorbed and is rapidly converted to its active metabolite, fenofibric acid. Fenofibrate is not detected in plasma. Fenofibric acid is primarily eliminated as a glucuronide conjugate in urine. The mean terminal disposition half-life of fenofibric acid is approximately 20 hours in subjects with normal renal function.1,2
Pravastatin is indicated as an adjunct to diet to reduce elevated total and LDL-C, apo B, and triglyceride levels and to increase HDL-C in patients with primary hypercholesterolemia, mixed dyslipidemia, and elevated serum triglyceride levels. Like all statins, pravastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis.3
A recent update of the National Cholesterol Education Program Adult Panel III guidelines recommends treatments combining statin and fibrate therapy in patients at high risk of coronary heart disease.4 These new guidelines may increase the use of statin-fibrate combination therapy.
In a previous study,5 concurrent administration of single doses of pravastatin and fenofibrate to healthy subjects produced no significant changes in fenofibric acid or pravastatin pharmacokinetics. Systemic exposure to the 3-hydroxy isomeric metabolite of pravastatin (3-hydroxy-iso-pravastatin) was modestly increased (less than 30%). This metabolite has 2.5% to 10% of the HMG-CoA reductase activity of the parent drug. Results of a previous long-term study suggested that fenofibrate and pravastatin may be safely administered together for as long as 2 years.6
The pharmacokinetic interaction between multiple doses of the fibrate drug, gemfibrozil, and a single 40-mg dose of pravastatin was examined in a study conducted by Kyrklund and coworkers.7 The AUC
of pravastatin when given with gemfibrozil was increased by 202% compared to the corresponding value during the placebo phase, and the renal clearance of pravastatin was reduced by 44% during gemfibrozil coadministration. Other pharmacokinetic drug-drug interaction studies have demonstrated that coadministration of gemfibrozil leads to significant increases in systemic exposure (AUC) to the active moiety of other statins, including simvastatin acid (185%),8 lovastatin acid (280%),9 and cerivastatin (559%).10
Given the likelihood that statin-fibrate combination therapy will increase and the significant pharmacokinetic interactions observed upon coadministration of multiple doses of gemfibrozil with several statins, the current study was designed to evaluate the potential effects of multiple doses of fenofibrate on the steady-state pharmacokinetics of pravastatin and its active metabolite, 3-hydroxy-iso-pravastatin. Given the lack of effect of a single dose of pravastatin on fenofibric acid pharmacokinetics,5 fenofibric acid pharmacokinetics was not examined in the current study.
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STUDY DESIGN AND PROCEDURES |
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TOPABSTRACTSTUDY DESIGN AND PROCEDURESRESULTSDISCUSSIONREFERENCES |
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The study was conducted in accordance with all applicable regulations and guidelines, as well as ethical principles that have their origin in the Declaration of Helsinki. The protocol was reviewed and approved by the independent ethics committee Ethikkommission der Landesärztekammer Rheinland-Pfalz. All subjects voluntarily provided written informed consent prior to the study.
Subjects took pravastatin (one 40-mg tablet qd) on the mornings of study days 1 to 15. Fenofibrate (one 160-mg tablet qd) was coadministered with the pravastatin dose on the mornings of study days 6 to 15. Each dose of the study drug was taken orally with approximately 240 mL of water 30 minutes after starting breakfast. The breakfast content was identical on the intensive pharmacokinetic sampling days (study days 5, 6, and 15). Subjects were confined to the study site and supervised for approximately 17 days.
Subjects received a standardized diet for all meals during confinement, which provided approximately 30% of the daily calories from fat. Subjects did not consume grapefruit, grapefruit products, alcohol, and/or caffeine during the study. Study site personnel performed hand and mouth checks to ensure ingestion of each dose. Blood samples (7 mL) were collected prior to dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing on study days 5, 6, and 15.
Plasma concentrations of pravastatin and 3-hydroxy-iso-pravastatin were determined at MDS Pharma Services (St Laurent, Quebec, Canada) using a validated liquid chromatography method and selected reaction monitoring tandem mass spectrometric detection. Briefly, pravastatin, 3-hydroxy-iso-pravastatin, and the isotopically labeled internal standard (pravastatin-D9) were extracted from human plasma by elution from preconditioned C-8 solid-phase extraction disks. The eluent was dried, reconstituted, and subjected to reversed-phase high-performance liquid chromatographic analysis on a 5-µm C-18 column. A PE Sciex API 3000 mass spectrometry system using a Turbo Ion Spray source was used to monitor mass transitions of 423.2 
321.0, 423.2 321.0, and 432.2 321.0 for pravastatin, 3-hydroxy-iso-pravastatin, and pravastatin-D9, respectively.
The calibration curves included 10 nonzero standards covering the linear range of the assay from approximately 0.10 to 100 ng/mL for both analytes. The lower limit of quantitation (LLOQ) for both analytes was set to the concentration of the lowest nonzero calibration standard, or approximately 0.10 ng/mL, using a 500-µL plasma sample. The precision of the assay was assessed using intra-assay and interassay coefficient of variation (CV) values. Intra-assay precision CVs for both analytes were 
7.1%, and interassay precision CVs for both analytes were 6.3%. The accuracy of the assay was assessed using mean analytical recovery values. Intra-assay recoveries for both analytes were between 95.4% and 99.5% of their theoretical values, and interassay recoveries for both analytes were between 93.3% and 100.3% of their theoretical values.
In-study quality control (QC) samples were supplemented with concentrations of approximately 0.3, 45, and 90 ng/mL of each analyte and were analyzed with the unknowns. The interassay precision CVs for the accepted data ranged from 2.4% to 11.1% and from 5.5% to 33.0% for pravastatin and 3-hydroxy-isopravastatin, respectively. The mean analytical recoveries ranged from 93.9% to 98.1% of their theoretical values for pravastatin and from 97.8% to 119.8% for 3-hydroxy-iso-pravastatin.
Values for the pharmacokinetic parameters of pravastatin and 3-hydroxy-iso-pravastatin were estimated using noncompartmental methods (WinNonlin-Professional, Version 4.1, Pharsight Corporation, Mountain View, Calif). Parameters included the maximum observed plasma concentration (Cmax), the time to Cmax (peak time, tmax), the minimum observed plasma concentration (Cmin), the area under the plasma concentration-time curve during a 24-hour dosing interval (AUC24), the terminal phase elimination rate constant (
z), and the corresponding terminal elimination half-life (t1/2). The AUC24 was calculated using the trapezoidal rule, and z was calculated from the slope of the least squares linear regression of the logarithms of the plasma concentration versus time data from the terminal log-linear phase of the profile. For pravastatin only, the apparent oral clearance (CL/F, where F is the bioavailability) was also calculated.
Paired t tests were performed for Cmax, AUC24, tmax, and z at a significance level of .05 to assess the effects of fenofibrate coadministration. Comparisons were made for each of study days 6 and 15 with study day 5 and for study day 15 with study day 6. Logarithmic transformation was employed for AUC24 and Cmax. No statistical analyses were performed for Cmin because the minimum concentrations were below the LLOQ for the majority of subjects for both analytes. The t tests were performed using PROC UNIVARIATE on SAS, Version 8.2 (SAS Institute, Cary, NC). The paired t test approach was preferred over analysis of variance (ANOVA) with post hoc comparisons and correction for multiple comparisons because the ANOVA required additional assumptions regarding the homogeneity of the variances of the dependent variables.
In connection with the paired t tests for the logarithms of AUC24 and Cmax, a point estimate and 90% confidence interval for exposure during fenofibrate coadministration relative to exposure for pravastatin alone were provided. The point estimate and confidence interval endpoints were obtained by exponentiating the point estimate and 90% confidence limits for the change in the logarithm mean.
The number and percentage of subjects reporting treatment-emergent adverse events were tabulated by the COSTART11 term and body system, with and without a breakdown by study segment (pravastatin alone and coadministration of pravastatin and fenofibrate). Laboratory test values and vital signs measurements that were outside of predefined ranges were identified and evaluated for clinical significance.
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RESULTS |
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TOPABSTRACTSTUDY DESIGN AND PROCEDURESRESULTSDISCUSSIONREFERENCES |
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No clinically significant physical examination results or vital signs measurements were observed during the course of the study, and clinical laboratory evaluation revealed no significant study drug-related changes. No serious adverse events or discontinuations due to adverse events were reported during the study. Results of other safety analyses, including individual subject changes, changes over time, and individual values for vital signs and ECGs, were unremarkable for each segment of the study.
Both pravastatin and fenofibrate were generally well tolerated by the subjects. Five (5/24, 21%) subjects reported at least 1 treatment-emergent adverse event (any event with onset after the first dose of study drug) during the study. All of the events occurred during the combination segment (pravastatin plus fenofibrate). The most common adverse event was headache (3 subjects, 13%). The adverse events were considered by the investigator to be possibly related or not related to the study drug and were mild or moderate in severity.
On average, pravastatin exposure (Figure 1) and 3-hydroxy-iso-pravastatin exposure (Figure 2) were higher after both single and multiple dosing of fenofibrate than when pravastatin was given alone. The mean ± SD pharmacokinetic parameters for pravastatin and 3-hydroxy-iso-pravastatin from study day 5 (pravastatin alone), study day 6 (pravastatin plus 1st dose fenofibrate), and study day 15 (pravastatin plus 10th dose fenofibrate) are presented in Table I.
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The point estimates and 90% confidence intervals for the ratios of the central values on study day 6 (pravastatin with 1st dose fenofibrate) to those on study day 5 (pravastatin alone), on study day 15 (pravastatin with 10th dose fenofibrate) to those on study day 5 (pravastatin alone), and on study day 15 (pravastatin with 10th dose fenofibrate) to those on study day 6 (pravastatin with 1st dose fenofibrate) are given for the pravastatin and 3-hydroxy-iso-pravastatin Cmax and AUC24 values in Table II. Changes in individual pravastatin and 3-hydroxy-iso-pravastatin AUC24 values are presented in Figure 3 and Figure 4, respectively. The ranges of individual AUC24 values for both pravastatin and 3-hydroxy-iso-pravastatin appear somewhat wider during coadministration of fenofibrate than during administration of pravastatin alone.
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DISCUSSION |
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TOPABSTRACTSTUDY DESIGN AND PROCEDURESRESULTSDISCUSSIONREFERENCES |
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-hydroxy-iso-pravastatin was modestly, but statistically significantly, increased (less than 30%, on average). In general, pravastatin pharmacokinetics was variable, and the CVs for pravastatin Cmax and AUC reported from this previous study exceeded 50%.5 This variability is consistent with the low oral bioavailability (approximately 18%) of pravastatin.3,12 In the current study, the effects of fenofibrate on multiple-dose pravastatin pharmacokinetics were examined following the 1st (study day 6) and 10th (study day 15) doses of fenofibrate. The dose of fenofibrate used to potentially modify pravastatin pharmacokinetics was the approved daily dose of the formulation used in this study.1 Increases in pravastatin systemic exposure following the first dose of fenofibrate were small (22% for Cmax and 19% for AUC24, on average) and consistent with those observed in the previous single-dose study.5 Following the 10th dose of fenofibrate, increases in pravastatin systemic exposure were slightly greater than those following the 1st dose of fenofibrate (36% for Cmax and 28% for AUC24, on average), but these apparent increases in pravastatin exposure from the 1st to the 10th dose of fenofibrate were not statistically significant. The slight increases from study day 6 to study day 15 may be due to the effects of higher fenofibric acid concentrations that would be expected upon multiple dosing of fenofibrate. Because fenofibric acid is eliminated with a half-life of about 20 hours,1,2 circulating plasma concentrations at steady state would be expected to be nearly double those following a single dose.
The effects of fenofibrate on the multiple-dose pharmacokinetics of 3-hydroxy-iso-pravastatin were also examined in the current study following the 1st and 10th doses of fenofibrate. Increases in 3-hydroxy-iso-pravastatin systemic exposure following the first dose of fenofibrate were modest (31% for Cmax and 24% for AUC24, on average) and similar to those observed in the previous single-dose study. Following the 10th dose of fenofibrate, increases in 3-hydroxy-iso-pravastatin systemic exposure were slightly greater than those following the 1st dose of fenofibrate (55% for Cmax and 39% for AUC24, on average), but these apparent increases in 3-hydroxy-iso-pravastatin exposure from the 1st to the 10th dose of fenofibrate were not statistically significant. The HMG-CoA reductase activity of 3-hydroxy-iso-pravastatin is 2.5% to 10% of the activity of the parent drug.3
The results of the current study are in sharp contrast to those from a study conducted by Kyrklund and coworkers,7 which examined the effect of another fibrate drug, gemfibrozil, on the pharmacokinetics of pravastatin. In a randomized, placebo-controlled, 2-phase crossover design, 10 healthy volunteers received 1200 mg of gemfibrozil or placebo once daily for 3 days (1200 mg is the approved daily dose of gemfibrozil).13 A single dose of 40 mg pravastatin was given on the third day. Plasma and urine concentrations of pravastatin were measured for 24 hours after pravastatin dosing. Pharmacokinetic parameters were calculated, including the AUC extrapolated to infinite time (AUC) and the renal clearance of pravastatin. The AUC of pravastatin when given with gemfibrozil was increased by 202% (range, 40%-413%) compared to the corresponding value during the placebo phase. The renal clearance of pravastatin was reduced by 44% during gemfibrozil coadministration. The authors concluded that the interaction between gemfibrozil and pravastatin was partly, but not solely, due to a reduction in the renal clearance of pravastatin. They also hypothesized that the increase in pravastatin AUC may be the result of inhibition of a transport protein.7
More recently, in vitro uptake studies have indicated that gemfibrozil and gemfibrozil glucuronide are inhibitors of the organic anion transporting polypeptide 2 (OATP2),14 a transporter present in the human liver for which pravastatin is a known substrate.15 Thus, inhibition of OATP2 by gemfibrozil or its glucuronide could be an additional mechanism by which gemfibrozil coadministration leads to increased systemic exposure for pravastatin.
Whatever the mechanism(s), the work of Kyrklund et al7 clearly shows that gemfibrozil coadministration leads to a substantially greater increase in pravastatin systemic exposure than fenofibrate coadministration does in the current study. Other pharmacokinetic drug-drug interaction studies have demonstrated that coadministration of gemfibrozil led to significant increases in systemic exposure (AUC) to the active moiety of other statins, including simvastatin acid (185%),8 lovastatin acid (280%),9 and cerivastatin (559%).10 A single dose of gemfibrozil did not significantly affect the pharmacokinetics of fluvastatin,16 but the effects of multiple doses of gemfibrozil on fluvastatin have not been reported.
Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to form the active moiety, fenofibric acid. Fenofibric acid is primarily eliminated via urinary excretion of the glucuronide conjugate. In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of CYP3A, CYP2D6, CYP2E1, and CYP1A2. Fenofibrate and fenofibric acid are weak inhibitors of CYP2C19 and CYP2A6 and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.1,2 Currently, it is unknown whether fenofibrate and/or fenofibric acid are substrates of any transporters or modify transporter activity.
The mechanisms of the observed effects of coadministration of fenofibrate on the pharmacokinetics of pravastatin and 3-hydroxy-iso-pravastatin are not readily apparent. In a study of the disposition of radiolabeled pravastatin,12 oral absorption of [14C] activity was about 34%, with about half of the [14C] activity absorbed as parent pravastatin. Approximately 20% of an oral dose was excreted in the urine, and 71% was excreted in the feces. Renal clearance of pravastatin averaged more than 400 mL/min, a value far in excess of glomerular filtration, indicating that tubular secretion was a predominant elimination mechanism. Even after intravenous administration, approximately 34% of a pravastatin dose was eliminated in the feces, indicating substantial biliary excretion.12 The importance of tubular secretion and biliary excretion in the elimination of pravastatin suggests that one or more transporters may play an important role in pravastatin elimination. For example, there is evidence to suggest that pravastatin is a substrate for OATP2,15 the organic anion transporting polypeptide-C (OATP-C),17-19 but not for the organic anion transporter 3 (OAT3).17
Many metabolic pathways have been elucidated for pravastatin,3,20 and 3-hydroxy-iso-pravastatin is both an acid degradation product and a metabolite of pravastatin.21 Unlike many other statins, the 3A isoform subfamily of cytochrome P450 (CYP3A) does not appear to be significantly involved in the metabolism of pravastatin.3,22 Coadministration of lopinavir/ritonavir23 has been shown to increase pravastatin systemic exposure, and ritonavir is known to inhibit the activities of both CYP3A and P-glycoprotein (Pgp or MDR1). Assuming that inhibition of CYP3A is not likely to affect the pharmacokinetics of pravastatin, it is possible that this interaction is mediated through inhibition of Pgp. Other in vitro research indicates that pravastatin is neither an inhibitor nor a high-efficiency substrate of Pgp.24
Competition with or modulation of OATP2, OATP-C, Pgp, and/or other transport proteins remains a potential mechanism for the modest increases in pravastatin and 3-hydroxy-iso-pravastatin systemic exposures observed with coadministration of fenofibrate in the current study.
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REFERENCES |
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TOPABSTRACTSTUDY DESIGN AND PROCEDURESRESULTSDISCUSSIONREFERENCES |
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14. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther. 2004;31: 228-236.
15. Hsiang B, Zhu Y, Wang Z, et al. A novel human organic anion transporting polypeptide (OATP2): identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. JBiol Chem. 1999;274: 37161-37168.
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17. Nishizato Y, Ieiri I, Suzuki H, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73: 554-565.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T. Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther. 2004;75: 415-421.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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22. Jacobsen W, Kirchner G, Hallensleben K, et al. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos. 1999;27: 173-179.
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