| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
DRUG INTERACTIONS |
From SFBC-New Drug Services Inc, Kennett Square, Pennsylvania (Dr Adams); HPP Consulting & Services Inc, Elkton, Maryland (Dr Pieniaszek); and Endo Pharmaceuticals Inc, Chadds Ford, Pennsylvania (Dr Gammaitoni, Dr Ahdieh).
Address for reprints: Harry Ahdieh, PhD, Director of Clinical Operations, Endo Pharmaceuticals Inc, 100 Painters Drive, Chadds Ford, PA 19317.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Key Words: CYP2C9 • CYP3A4 • opioid • oxymorphone extended release • drug interactions
Opioids undergo differential metabolism by the CYP450 system, primarily through the CYP3A4 and CYP2D6 pathways, and/or by uridine 5'-diphosphate-glucuronosyltransferases, producing active and inactive metabolites.7,8 The CYP450 enzymes most commonly involved in human drug metabolism are 3A, 2D6, and 2C, which are believed to be the enzymes principally responsible for the metabolism of 36%, 19%, and 16% of all marketed drugs metabolized by CYP450 enzymes, respectively.9 Use of concomitant medications metabolized by the same CYP450 enzyme may alter the plasma levels of 1 or both drugs, particularly if 1 drug has a higher affinity for the enzyme, has similar affinity but is present at a higher molar concentration, or binds noncompetitively to inhibit or induce enzyme activity. Patients who require opioids for the control of chronic pain are often treated with multiple CYP450-metabolized medications for their primary disease, thereby potentially complicating the management of pain.
Despite low reactivity in vitro with CYP2C9 and CYP3A4 at suprapharmacologic concentrations only, it was important to determine in vivo whether oxymorphone ER has the potential to interact with drugs metabolized by these 2 pathways. Two single-center, randomized, open-label, parallel-group studies compared the effects of a new oral oxymorphone ER formulation, using 2 dosage levels, on the metabolism of oral tolbutamide (study 1) and oral midazolam plus intravenous erythromycin (study 2), known substrates of CYP2C9 and CYP3A4, respectively.10
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Subjects
Each study enrolled nonsmoking healthy men and women who were 18 to 55 years of age and of normal body weight (ie, 
45.5 kg and within 15% of standard weight). Women who were pregnant or breast-feeding were not eligible to participate, and those of child-bearing potential were required to use a medically acceptable nonoral form of contraception for the study duration. Potential participants known or suspected of recent or prior opioid abuse were excluded. Exclusion criteria also included hypersensitivity to any of the study medications or probes; a positive screen for hepatitis B, hepatitis C, or human immunodeficiency virus; history or presence of diabetes mellitus or hypoglycemia (specified for study 1 only); history of pulmonary disease; a history of alcohol abuse, illicit drug use, or any other drug abuse or addiction; or a positive urine drug screen for ethanol or illicit drugs.
Concurrent administration of CYP450 2C9 or 3A4 substrates, inhibitors, or inducers (other than those administered as part of the study) at any time during the trials was prohibited.10 Prescription and over-the-counter (OTC) medications also were not permitted, beginning 2 weeks and 24 hours before the first dose of study medication, respectively; this exclusion was extended to 4 weeks for any prescription drug known to be a substrate, inducer, or inhibitor of the CYP450 pathway being evaluated. In both studies, consumption of alcoholic beverages within 72 hours before the first dose of study medication was prohibited.
Investigators were permitted to authorize short-term use of an OTC product for a self-limiting indication. Any medication taken by a subject during the study was recorded.
Treatment Administration
Eligible subjects were randomly assigned to 1 of the 5 treatment groups. On days –1, 7, and 14, all subjects received a single dose of the CYP450 probes, that is, one 500-mg tolbutamide tablet PO (Fisher Scientific, Hampton, NH) in study 1 and midazolam HCl syrup 2 mg (Fisher Scientific, Hampton, NH) PO plus 3 µCi [14C N-methyl]-erythromycin (Metabolic Solutions, Nashua, NH) 
0.03 mg intravenous push in study 2. The latter dual-probe approach was chosen to distinguish combined systemic and presystemic CYP3A4 activities from systemic CYP3A4 activity only.11 Subjects received high-dose oxymorphone ER (Endo Pharmaceuticals Inc, Chadds Ford, Pa) plus naltrexone (DuPont Pharmaceuticals, Wilmington, Del), low-dose oxymorphone ER alone, rifampin (Fisher Scientific, Hampton, NH) (active control), naltrexone alone, or probes only (untreated control) for up to 18 days, as outlined in Figure 1. Because the high-dose oxymorphone ER group was administered the opioid antagonist naltrexone to prevent opioid-related adverse events, a naltrexone-only arm was included to control for the potential effects of naltrexone on the pharmacokinetics of the test probes.
|
To mitigate the potential hypoglycemic effects of tolbutamide, subjects in study 1 received a high-carbohydrate breakfast approximately 1.5 hours before administration of each tolbutamide dose on days –1, 7, and 14; 8 ounces of pulp-free orange juice 1 hour after administration; and a standard luncheon approximately 4 hours after administration.
Sample Collection
Venous blood samples were collected in 7-mL ethyl-enediaminetetraacetic acid tubes immediately before morning dose administration of test medications and probes (time 0) and at 1, 2, 3, 4, 6, 8, and 12 hours on days –1, 7, and 14 for tolbutamide or midazolam and on day 14 for oxymorphone ER. Additional samples were collected at 24 hours for tolbutamide and at 0.25 and 0.5 hours for midazolam.
In study 1, urine samples were collected immediately before tolbutamide administration on days –1, 7, and 14 for analysis of the urinary hydroxytolbutamide: tolbutamide (H:T) ratio. Urine samples also were collected through 24 hours after each dose of study medication. All urine was collected in polypropylene containers without added preservatives and kept frozen until analysis. In study 2, 2 breath samples of expired air were obtained in 3-L polyester collection bags immediately before and 20 minutes after the injection of the [14C N-methyl]-erythromycin dose on days –1, 7, and 14.
Analytical Methods
Oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide. Plasma concentrations of oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide were determined with parallel high-performance liquid chromatography (HPLC) combined with tandem mass spectrometry (parallel LC/MS/MS). Two methods have been developed and validated by SFBC Analytical Laboratories, Inc (North Wales, Pa). Oxymorphone and 6-OH-oxymorphone concentrations were determined following a liquid-liquid extraction from alkalinized human plasma: 50 µL of 50% acetonitrile (v/v), 50 µL of d3-oxymorphone and d3-6-OH-oxymorphone internal standards, and 1 mL of 0.2 N ammonium hydroxide were added to 0.5 mL of plasma. After vortexing for 10 seconds, the sample received 4 mL of methyl-t-butyl ether (MTBE) and was capped and vortexed for 2 minutes. The sample was centrifuged at 3000g for 6 minutes at room temperature to separate the phases. Three milliliters of the organic phase was transferred to a new tube, evaporated under nitrogen in a 40°C water bath, reconstituted in 150 µL of HPLC mobile phase (50% acetonitrile/50% of 0.1% formic acid in water), and vortexed for 20 seconds. A 10-µL aliquot was injected into a PE SCIEX API 3000 series LC/MS/MS system (MDI SCIEX, Concord, ON, Canada). The MS/MS detector with a turbo ion spray interface operating in the positive ionization mode monitored the transition ions m/z 302 
284, m/z 304 286, m/z 305 287, and m/z 307 289 for oxymorphone and 6-hydoxy-oxymorphone and their inernal standards, respectively. The linear range of quantitation for oxymorphone and 6-OH-oxymorphone was 0.1 to 20 ng/mL plasma.
Oxymorphone-3-glucuronide concentrations were determined following solid-phase extraction (SPE) from acidified human plasma: 100 µL of d3-oxymorphone-3-glucuronide internal standard and 2 mL of 0.1% trifluoroacetic acid (TFA) were added to 0.5 mL of plasma. Samples were vortexed and centrifuged at 2000g for 5 minutes at room temperature, and the supernatant was applied to an SPE column. Before sample application, the SPE columns were equilibrated by successive 3-mL gravity washes with methanol, water, and 0.1% TFA. After sample application, columns were washed by gravity with 2 mL of 0.1% TFA, dried under a vacuum for 60 seconds, and eluted with 3 mL of 50% methanol (v/v). The eluant was dried under nitrogen in a 55°C water bath, reconstituted in 150 µL of HPLC mobile phase (90% acetonitrile/10% with 10 mL/L formic acid), and vortexed for 30 seconds; 20 µL was injected into the LC/MS/MS system (using a PE SCIEX API 300). The MS/MS detector with a turbo ion spray interface operating in the positive ionization mode monitored transition ions m/z 478.4 284 and m/z 481.4 287 for oxymorphone-3-glucoronide and its internal standard, respectively. The linear range of quantification for oxymorphone-3-glucuronide was 5 to 250 ng/mL of plasma. Least squares linear regression modeling was performed to calculate the calibration curves.
Specificity of the procedures was established by determining the chromatographic profiles of purified standards of oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide as well as for d3-labeled analytes and then ensuring that (1) there was no interference from control plasma and (2) the chromatographic profile of each analyte (including naltrexone) did not interfere with the other analytes. For example, the oxymorphone-3-glucuronide standard and the d3-labeled compound produced peaks at m/z 478.4 284 and 481.4 287, respectively. These peaks were not produced by control plasma or by the other analytes, including naltrexone. The limits of quantification (with acceptable regulatory validation criteria) for oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide were 0.1 to 20 ng/mL, 0.1 to 20 ng/mL, and 5 to 250 ng/mL, respectively. Precision (percentage of coefficient variation for the standard curves of the validation samples) was 1.91% to 6.95%, 2.26% to 17.42%, and 0.93% to 3.01% for oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide, respectively, in study 1. In study 2, the values were 2.17% to 5.15%, 0.67% to 5.89%, and 1.23% to 4.61% for oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide, respectively.
Plasma concentrations of tolbutamide or midazolam. Plasma concentrations of tolbutamide or midazolam were measured by a validated LC/MS/MS method. For midazolam determination, human plasma samples containing the internal standard, desmethyldiazepam, were adjusted to alkaline pH with ammonium hydroxide and extracted into a mixture of 3:1 MTBE:hexane. The organic phase was dried under nitrogen at 40°C and reconstituted in water:acetonitrile (75:25, v/v). The samples were chromatographed on reversed-phase HPLC using a SB-Phenyl, Zorbax, Agilent column (150 x 2.1 mm, 5 µm) maintained at 40°C. The mobile phase was nebulized using heated nitrogen in a Z-spray source/interface, and the ionized compounds were monitored by a tandem quadrupole mass spectrometer operating in the positive electrospray ionization mode (Quattro Ultima, Micromass, Beverly, Mass). The transition ions m/z 325.8 291.1 and m/z 270.8 139.8 were monitored for midazolam and desmethyldiazepam. The calibration range of the method was from 0.500 to 250.0 ng/mL.
For tolbutamide determination, human plasma containing the internal standard, chlorpropamide, was deproteinized by precipitation with acetonitrile, and an aliquot of the supernatant was chromatographed on reversed-phase HPLC using a Synergi Polar RP column (150 x 2.00 mm, 4 µm) maintained at 45°C. The mobile phase was nebulized using heated nitrogen in a Z-spray source/interface, and the ionized compounds were monitored by a tandem quadrupole mass spectrometer operating in the positive electrospray ionization mode (Quattro Ultima, Micromass, Beverly, Mass). The transition ions m/z 270.9 155.0 and m/z 276.8 174.9 were monitored for tolbutamide and chlorpropamide, respectively. The calibration range of the method was from 0.100 to 20.0 µg/mL. Precision was 4.0% to 7.5% and 5.4% to 7.8%.
Urine concentrations of tolbutamide and 4-hydroxytolbutamide. Urine samples and standards containing the internal standard, chlorpropamide, were diluted with a water:acetonitrile and formic acid solution (25:75:0.1, v/v/v). The mixture was vortex mixed, and a portion of the diluted sample was chromatographed on reversed-phase HPLC using a Luna C18 Phenomenex column (150 x 2.00 mm, 5 µm) maintained at 45°C. The mobile phase was nebulized using heated nitrogen in a Z-spray source/interface, and the ionized compounds were monitored by a tandem quadrupole mass spectrometer operating in the positive electrospray ionization mode (Quattro Ultima, Micromass, Beverly, Mass). The transition ions m/z 270.9 155.2, m/z 287.1 171.2, and m/z 277.0 174.9 were monitored for tolbutamide, 4-hydroxytolbutamide, and chlorpropamide. The calibration range of the method was from 0.100 to 20.0 µg/mL. Precision was 2.9% to 5.9% and 3.6% to 9.7% for urinary tolbutamide and 4-hydroxytolbutamide, respectively.
Erythromycin breath test. The amount of expired 14CO2 in breath samples collected during the erythromycin breath test (ERMBT) was determined by a validated liquid scintillation technique (Metabolic Solutions, Nashua, NH). The breath samples collected in the 3-L polyester collection bags were pumped through a carbon dioxide trapping solution of 2 mL 1 M hyamine hydroxide in methanol, 2 mL ethanol, and 1 drop of thymolphthalein indicator solution in scintillation vials. The gas from the collection bags was bubbled into the trapping solution until the color turned from blue to completely clear. After the addition of 10 mL Poly-Fluor scintillation fluid to the scintillation vial, the vials were stored in the dark for a minimum of 24 hours, and then the activity of 14C was determined by scintillation spectrometry (Packard Instrument Co, Meriden, Conn; Tri-Carb model 2100TR); internal standards were low-level 14Cand 14C toluene. The percentage of administered 14CO2 exhaled in the first hour was calculated from the 20-minute time point, with the percentage of 14CO2 exhaled over 1 hour (%14CO2/h) being the parameter of interest. The limit of quantitation was 5 dpm for values assessed at 40 to 50 and 320 to 350 dpm. The short-term intrarun precision on breath samples was 1.5%.
Pharmacokinetics
Pharmacokinetic variables were calculated from plasma tolbutamide, midazolam, and oxymorphone concentration data using standard noncompartmental methods (Kinetica, Innophase Corporation, West-brook, Conn). The highest observed plasma concentration during the dosage interval was defined as Cmax, the time that Cmax was observed was defined as tmax, and the terminal elimination half-life was defined as t
and was calculated as 0.693/
z. AUC was defined as the area under the concentration versus time curve from time 0 to infinity and was calculated as AUCT + Ct/z, and oral clearance (Clo) was calculated as dose/AUC.
Safety Assessments and Adverse Event Reporting
The studies assessed safety by adverse event (AE) monitoring, clinical laboratory evaluations (including serum chemistry, hematology, and urinalysis), routine vital signs, and physical examination findings. Electro-cardiograms were obtained during the studies if clinically indicated. In study 2, oxygen saturation was also measured for subjects in the oxymorphone groups. In study 1, a rapid peripheral technique was used to monitor blood sugar 2 hours after probe administration and as clinically indicated.
Adverse events were carefully monitored and categorized based on severity (mild, moderate, severe, or life threatening) and relationship to study medication (unrelated, possibly related, or probably related). Treatment-related AEs were those considered to be "possibly" or "probably" related to the study medication.
Statistical Analyses
Both studies used the same statistical methodology. Target sample sizes were based on the intrapatient variability of tolbutamide, midazolam, and ERMBT in previous studies.11,12 It was determined that 12 subjects per treatment group were required to provide 80% power at a 2-sided significance level of 5% for a between-treatment difference of 50%; however, to account for potential withdrawals, 16 subjects were enrolled into each treatment group. Pharmacokinetic parameters and laboratory results, vital signs, and other safety variables were summarized by treatment group using descriptive statistics (mean, standard deviation, coefficient of variation, median, and range). SAS software (version 8.2) (Cary, NC) was used for all statistical analyses and, unless otherwise specified, P 
.05 was used for establishing statistical significance for all between-group comparisons.
All subjects who completed 14 days of their randomized study treatment and had both baseline and day 14 probe results were included in the pharmacokinetic analyses (subject must have had a Cmax and z in study 1). Pharmacokinetic analyses compared the change from baseline to day 14 for the probe AUCs between the high-dose (group A) and low-dose (group B) oxymorphone ER treatment groups and the untreated control group (group E). These analyses used a fixed-effects analysis of variance, using treatment as the fixed effect, and Dunnett's multiple-comparison procedure. Additional analyses included comparison of change from baseline to day 14 for probe AUC between each of the rifampin and naltrexone treatment groups (groups C and D, respectively) and untreated control (group E); comparison of change from baseline to day 7 for probe between each treatment group and the untreated control; summary of the time course of the effect (eg, the relative difference between change from baseline to day 7 and change from baseline to day 14); examination of the change from baseline to day 14 for the probe pharmacokinetic parameters; and summary of the pharmacokinetics of the low- and high-dose oxymorphone ER treatments and an examination of dose proportionality. In addition, in study 1, change from baseline to day 14 for the urine H:T ratio was compared between each treatment group and the untreated control.
The safety population consisted of all subjects who received at least 1 dose of randomized study medication plus all subjects randomized to the untreated control group. Baseline was defined as the last measurement before the first dose of randomized study medication. The frequency of AEs, serious AEs, treatment-related AEs, and AEs by maximum severity were summarized by system organ class and preferred term.13 The numbers and percentages of subjects who experienced at least 1 AE were calculated by treatment group.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Twelve subjects discontinued study 1 before completion because they no longer wanted to participate (n = 8), developed an AE (n = 3), or had a family emergency resulting in consent withdrawal (n = 1). There were 2 early withdrawals in study 2, both of which were attributed to AEs.
Pharmacokinetic Results
Pharmacokinetic analyses captured data for 73 and 78 subjects in studies 1 and 2, respectively. In the oxymorphone ER and naltrexone groups, changes from baseline to day 14 in tolbutamide and midazolam AUCs (Table I) and the percentage of expired 14CO2/h in the ERMBT were minimal and not statistically significant compared with those seen in the untreated controls. Conversely, from baseline to day 14, rifampin significantly decreased tolbutamide and midazolam AUCs by 61% and 84%, respectively, and increased the percentage of 14CO2 expired/h by 121% (P <.05 in all cases). Similar results were obtained on day 7, indicating that maximum induction of CYP2C9 and CYP3A4 activities occurred by day 7.
|
Urinary analysis of the H:T ratio showed that only treatment with rifampin caused a significant change (120% increase, P < .05) from baseline to day 14. The largest decreases in Cmax when using tolbutamide as a probe for CYP2C9 activity occurred in response to rifampin (Table I). A smaller decrease was observed for low-dose oxymorphone ER but not for high-dose oxymorphone ER plus naltrexone (Table I). When midazolam was used as a probe for CYP3A4 activity, only subjects who received rifampin exhibited a large and significant decrease in Cmax (Table I). As with tolbutamide, a small decrease in Cmax was observed in low-dose oxymorphone ER, but a similar decrease was observed with the untreated group, indicating that an approximate 10% change represents normal variation. Significant changes in t were observed only with rifampin treatment, mirroring the results with AUC and Cmax (Table I). Changes in tmax varied by up to 24% in the untreated control groups, and changes in tmax in the other treatment groups were of similar or lesser magnitude (data not shown).
Dose Proportionality
The AUCs and Cmax of oxymorphone ER, 6-OH-oxymorphone, and oxymorphone-3-glucuronide each increased at steady state on day 14 in a dose-proportional manner in both studies, whereas tmax was not significantly affected by dose. Results from study 2 are shown in Table II.
|
Safety Results
No serious AEs occurred during either study. Most treatment-related AEs reported by subjects taking oxymorphone were mild in severity and characteristic of opioid therapy (constipation, nausea, vomiting, and headache) and caused 2 study withdrawals. No clinically significant changes in laboratory tests, vital signs, or physical findings were observed, except for a single subject developing hypertension postbaseline that was unlikely related to study medication. In study 1, 4 subjects developed AEs consistent with symptoms of tolbutamide-induced hypoglycemia (all mild in intensity and resolved without sequelae), and 32 additional patients developed grade 2 hypoglycemia 2 hours after tolbutamide in the absence of hypoglycemic symptoms.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
In an effort to minimize variability, the studies were designed as parallel-group trials in which the primary comparison was change from baseline to day 14 for each treatment group compared with the untreated control group. Opioids are used at widely differing concentrations in different clinical settings. Given the potential for dose- or concentration-dependent enzymatic induction, testing a high clinical dose of oxymorphone in these trials was important. Because of dose-limiting effects on respiratory and central nervous system function, administering more than 20 mg of oxymorphone ER every 12 hours to opioid-naive subjects is not advisable.
Naltrexone is an established opioid antagonist used for blocking the clinical effects of opioid agonists. Although results from a prior clinical trial of oxymorphone ER 20 mg found that concurrent naltrexone 50 mg does not significantly alter oxymorphone pharmacokinetics, 6 the impact of naltrexone on hepatic enzyme activity has not been elucidated, prompting the inclusion of a naltrexone-only treatment group. Naltrexone did not appear to induce or inhibit metabolic activity in either study, and as expected, rifampin was shown to be a potent inducer of both CYP450 enzymes. Interestingly, there was a 20% variability for tolbutamide in tmax and nearly a 10% change in t and Cmax among the untreated control subjects, underscoring the importance of using an untreated control arm within pharmacokinetic trials to account for variation in CYP450 activity and to better compare the effects of the active control.
Most previous clinical experience with oxymorhone is based on nonoral formulations that are principally metabolized by the liver. However, significant drug metabolism by CYP3A4 occurs in both gut-associated and hepatic compartments.11 With the sensitive dual-probe approach used in study 2, it is possible to rule out significant induction or inhibition of CYP3A4 by oxymorphone ER at steady state in either compartment.
Drug interactions are estimated to incur costs in excess of $1 billion annually by increasing hospital admissions or length of stay.14,15 Overall, these studies demonstrate that oxymorphone ER has no effect on CYP2C9 or CYP3A4 at steady state, indicating that oxymorphone ER has a low potential for altering the plasma levels of other drugs metabolized by these enzyme pathways. In view of these results, it may be of further clinical interest to compare the potential for drug interactions of other widely prescribed opioids (such as dihydrocodeine, fentanyl, methadone, and oxycodone) with that of oxymorphone ER. Given that many patients receiving opioid therapy for chronic pain are treated concurrently with other medications, and drug-drug interactions may compromise the goals of pain management, oxymorphone ER provides a new option for clinicians that may mitigate these polypharmacy-related challenges in patients with moderate to severe pain.
|
FOOTNOTES |
|---|
Submitted for publication February 24, 2004; Revised version accepted October 10, 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Sinatra RS, Hyde NH, Harrison DM. Oxymorphone revisited. Semin Anesth. 1988;7: 209-215.
2. Eddy NB, Lee LEJ. The analgesic equivalence to morphine and relative side action liability of oxymorphone (4-hydroxydihydro-morphinone). J Pharmacol Exp Ther. 1959;125: 116-121.
3. Pharmaceuticals P. TIMERx control release delivery systems. Available at: http://www.penwest.com/timerx.html. Accessed January 10, 2005.
4. Adams MP, Ahdieh H. Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Pharmacotherapy. 2004;24: 468-476.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Data on file. Endo Pharmaceuticals Inc. Chadds Ford, Pa, 2001.
6. Data on file. Endo Pharmaceuticals Inc. Chadds Ford, Pa, 2002.
7. Lotsch J, Skarke C, Tegeder I, Geisslinger G. Drug interactions with patient-controlled analgesia. Clin Pharmacokinet. 2002;41: 31-57.
8. Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol. 2001;21: 500-515.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Rogers JF, Nafziger AN, Bertino JS Jr. Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs. Am J Med. 2002;113: 746-750.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Flockhart DA. Cytochrome P450 drug interaction table. Available at: http://medicine.iupui.edu/flockhart/. Accessed May 30, 2003.
11. McCrea J, Prueksaritanont T, Gertz BJ, et al. Concurrent administration of the erythromycin breath test (EBT) and oral midazolam as in vivo probes for CYP3A activity. J Clin Pharmacol. 1999;39: 1212-1220.[Abstract]
12. Madsen H, Enggaard TP, Hansen LL, Klitgaard NA, Brosen K. Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide. Clin Pharmacol Ther. 2001;69: 41-47.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. International Conference on Harmonization. Medical Dictionary for Regulatory Activities (MedDRA). Available at: http://www.meddramsso.com/. Accessed January 7, 2005.
14. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. JAMA. 1997;277: 301-306.
15. Johnson JA, Bootman JL. Drug-related morbidity and mortality: a cost-of-illness model. Arch Intern Med. 1995;155: 1949-1956.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Shou, M. Hayashi, Y. Pan, Y. Xu, K. Morrissey, L. Xu, and G. L. Skiles Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction Drug Metab. Dispos., November 1, 2008; 36(11): 2355 - 2370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W Chamberlin, M. Cottle, R. Neville, and J. Tan Oral Oxymorphone for Pain Management Ann. Pharmacother., July 1, 2007; 41(7): 1144 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Sinatra Opioid Analgesics in Primary Care: Challenges and New Advances in the Management of Noncancer Pain J Am Board Fam Med, March 1, 2006; 19(2): 165 - 177. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
