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1.  Simplified method for determination of clarithromycin in human plasma using protein precipitation in a 96-well format and liquid chromatography-tandem mass spectrometry 
A simplified method to determine clarithromycin concentrations in human plasma using protein precipitation in a 96-well plate and liquid chromatography tandem mass spectrometry was developed and validated. Plasma proteins were precipitated with acetonitrile and roxithromycin was used as the internal standard. After vortex-mixing and centrifugation, the supernatants were directly injected onto a Phenomenex Luna Phenyl-Hexyl column (50 × 2.0 mm I.D., 3μm). The mobile phase consisted of water and methanol (30:70; v/v) containing 0.1% formic acid and 5 mM ammonium acetate. The flow rate was 0.22 mL/min and the total run time (injection to injection) was less than 3 minutes. Detection of the analytes was achieved using positive ion electrospray tandem mass spectrometry in selected reaction monitoring (SRM) mode. The linear standard curve ranged from 100 to 5,000 ng/mL and the precision and accuracy (inter- and intrarun) were within 8.3% and 6.3%, respectively. The method was successfully used to determine clarithromycin concentrations in human plasma samples obtained from healthy subjects who were given clarithromycin 500 mg for three days. The method is rapid, simple, precise and directly applicable to clarithromycin pharmacokinetic studies.
doi:10.1016/j.jchromb.2008.06.050
PMCID: PMC3832059  PMID: 18639501
clarithromycin; roxithromycin; protein precipitation; LC-MS; human plasma
2.  Effect of Cytochrome P450 3A5 Genotype on Atorvastatin Pharmacokinetics and Its Interaction with Clarithromycin 
Pharmacotherapy  2011;31(10):942-950.
Study Objective
To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin.
Design
Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study.
Setting
Clinical research center at a teaching hospital.
Subjects
Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors).
Intervention
In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days.
Measurements and Main Results
Pharmacokinetic parameters of both forms of atorvastatin—atorvastatin acid and atorvastatin lactone—were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin’s muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8–64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6–42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC0−∞ of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049).
Conclusion
Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.
doi:10.1592/phco.31.10.942
PMCID: PMC3712822  PMID: 21950641
cytochrome P450; CYP; CYP3A5 genotype; pharmacogenetics; atorvastatin; clarithromycin; drug interaction
3.  Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants 
Pharmacotherapy  2011;31(12):10.1592/phco.31.12.1192.
Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration–cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available.
doi:10.1592/phco.31.12.1192
PMCID: PMC3655546  PMID: 22122181
warfarin; polymorphism; dabigatran; genotype; pharmacogenetics; cytochrome P450; CYP2C9 gene; vitamin K epoxide reductase complex subunit 1; VKORC1 gene
5.  β-Blocker pharmacogenetics in heart failure 
Heart failure reviews  2008;15(3):187-196.
β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients.
doi:10.1007/s10741-008-9094-x
PMCID: PMC2851851  PMID: 18437562
Pharmacogenetics; β-Blockers; Heart failure; Metoprolol; ADRB1; ADRB2
6.  Addressing The Challenges Of The Clinical Application Of Pharmacogenetic Testing 
Pharmacogenomics aims to use molecular genetic markers to predict treatment outcome. Indeed within the past decade, there has been a rapid emergence of pharmacogenetic tests to aid clinicians to predict efficacy or toxicity for some drugs. Despite this major advance in therapeutic drug management there remain challenges to the appropriate use of pharmacogenetic tests. We discuss UGT1A1 pharmacogenetic testing to illustrate the knowledge gaps impeding widespread use of pharmacogenetic tests in the clinical setting.
doi:10.1038/clpt.2009.30
PMCID: PMC2910521  PMID: 19536122
7.  Pharmacogenetics of β-Blockers 
Pharmacotherapy  2007;27(6):874-887.
β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice.
doi:10.1592/phco.27.6.874
PMCID: PMC2735790  PMID: 17542770
pharmacogenetics; β-blockers; hypertension; heart failure; atenolol; metoprolol; β1-adrenergic receptor gene; ADRB1; cytochrome P450 2D6 gene; CYP2D6
8.  Association of Diurnal Blood Pressure Pattern with Risk for Hospitalization or Death in Men with Heart Failure 
Journal of cardiac failure  2007;13(8):656-662.
Background
An altered diurnal blood pressure (BP) pattern has been linked to risk of developing heart failure (HF). We tested whether an altered diurnal BP pattern is associated with adverse outcomes (hospitalization due to HF exacerbation or death) in HF patients.
Methods and Results
One hundred eighteen HF patients were enrolled from a tertiary care HF clinic and followed for death or heart failure hospitalization for up to 4 years. 24-hour ambulatory BP was monitored. Forty patients (34%) had normal BP dipping pattern (night-day ambulatory BP ratio < 0.9), 44 (37%) had a non-dipping pattern (0.9 ≤ night-day ambulatory BP ratio < 1.0) and 34 (29%) had a reverse dipping BP pattern (night-day ambulatory BP ratio ≥ 1.0). A total of 39 patients had an adverse outcome. Adverse outcome rates were the lowest in dippers and the highest in reverse dippers (Log rank p=0.052). Predictors of adverse outcomes, selected based on log likelihood contrast, were NYHA functional class (Hazard ratio (HR) 1.96, 95% confidence interval (CI) 1.11-3.44), anemia (HR 2.50, 95% CI 1.23-5.08) and dipping status (HR 1.65, 95% CI 1.08-2.50).
Conclusions
In addition to other traditional predictors, blood pressure dipping status may be an important prognostic factor in HF.
doi:10.1016/j.cardfail.2007.04.013
PMCID: PMC2655230  PMID: 17923358
9.  A Summer Research Training Program to Foster PharmD Students' Interest in Research 
Objectives
To establish and assess the effectiveness of a 10-week summer research program on increasing doctor of pharmacy (PharmD) students' interest in research, particularly as it related to future career choices.
Design
Survey instruments were sent to 25 participants who had completed the research program in the summer of 2004, 2005, or 2006 to assess their satisfaction with the program and its influence on their career choices after graduation.
Assessment
Respondents reported a high degree of satisfaction with the program, indicating that the program allowed them to determine their suitability for a career in research, and 55% reported their intention to pursue additional research training.
Conclusion
A brief introduction to the clinical research environment helped pharmacy students understand the clinical sciences and careers in research. The introduction increased the likelihood of students pursuing a research career path after obtaining their PharmD degree.
PMCID: PMC2384198  PMID: 18483591
research; career; students

Results 1-9 (9)