Volume 42, No. 6/2004(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacodynamics
Influence of rifampin on serum markers of cholesterol and bile acid synthesis in men
Abstract
D. Lütjohann1, C. Hahn2, W. Prange1, T. Sudhop1, M. Axelson3, T. Sauerbruch2, K. von Bergmann1 and C. Reichel2
1Department of Clinical Pharmacology, University of Bonn, 2Department of Internal Medicine I, University of Bonn, Germany, and
3Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden
Objective: It has been demonstrated in preliminary studies that rifampin, a semisynthetic antibiotic and known inducer of hepatic cytochrome P450 3A4, reduces serum concentrations of total bile acids only in individuals with liver disease and elevated serum bile acid levels. Methods: We studied the effect of rifampin on concentrations of surrogate serum markers of cholesterol and bile acid synthesis as well as of cholesterol absorption in 10 male subjects before and after administration of rifampin (600 mg/day) for 6 days. Cholesterol and its precursors were analyzed by gas-liquid chromatography (GLC), bile acid intermediates and individual bile acids by isotope-dilution methods using GLC-mass spectrometry (MS) or by high-performance liquid chromatography (HPLC). Results: Treatment with rifampin resulted in a 70% increase (p = 0.008) of the serum concentration of the bile acid precursor 7a-hydroxy-4-cholesten-3-one, which is a marker for bile acid production. Serum total cholesterol was not altered, however, treatment with rifampin elevated the ratio of lathosterol to cholesterol, an indicator of cholesterol synthesis, by 23% (p = 0.037). Interestingly, serum concentration of total bile acids decreased slightly by 29% (p = 0.022), mainly due to a lowering of the secondary bile acid, deoxycholic acid (–60%; p = 0.005). Conclusion: A 6-day treatment with rifampin induces a reduction of deoxycholic serum concentrations in healthy men associated with a moderate increase of serum markers of bile acid and endogenous cholesterol synthesis.
Pharmacodynamics
Effects of high altitude exposure on the pharmacokinetics of furosemide in healthy volunteers
Abstract
A. Arancibia1, M. Nella Gai1, C. Paulos1, J. Chávez1, E. Pinilla1, N. Angel1 and W.A. Ritschel2
1Faculty of Chemical and Pharmaceutical Sciences, University of Chile, and 2Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Ohio, USA
Introduction: A cascade of pathophysiological events occurs with the ascension to high altitude (H). We have performed studies on the effects of exposure to H on the pharmacokinetics of drugs. The hypothesis behind these studies has been that the exposure to H, which produces marked physiological changes in the body, may alter pharmacokinetics, and consequently, pharmacodynamics. Our previous studies suggest that drugs highly bound to plasma proteins are most likely to exhibit altered disposition. Objective: In continuation of our research, we selected furosemide which is about 98% bound to plasma proteins, renally excreted and has low binding to red blood cells. Subjects, materials and methods: Furosemide (40 mg) was administered orally to 3 groups of young healthy volunteers. One group who had been residing at sea level (group L), the same group after 15 hours of exposure to high altitude (3,600 m, group HA) and a group of volunteers living at H for at least 6 months (group HC). Results: Our results are in accordance with the most recent pharmacokinetic studies on furosemide in which a terminal half-life of approximately 20 – 30 h was reported. Total proteins were 9.3% and 12.7% higher in groups HA and HC, respectively, than in group L. Albumin in group HC was 8.2% higher than group L. Bilirubin increased 17.7% and 41.2% in groups HA and HC, respectively, in comparison with group L. A rapid disposition rate constant in groups HA and HC was the only pharmacokinetic parameter that was significantly different from those in group L. Concentration of furosemide in plasma water increased significantly after H exposure, thus, the binding diminished from 97.2% in group L to 95.1% and 91.1% in groups HA and HC, respectively. Conclusion: Exposure to H produces an increase in the free fraction of furosemide in humans, which could be of therapeutic importance.
Adverse drug reactions
Adverse effect of drug-induced emotional problems on work and daily activities. A principal component as an independent predictor of ADRs in Shanghai patients with osteoarthropathy taking nabumetone
Abstract
W. Shi, Y.M. Wang, S.L. Li and M. Yan
1,2Department of Pharmacology, Fudan University, Shanghai, China, and 3,4The Center for Drug Re-evaluation and The Center for Adverse Drug Reaction Monitoring, State Food and Drug Administration, Beijing, China
Objective: To discover principal components among assessed items from the WHO-SF36 survey by principal component analysis (PCA) and then to establish the relationship between the candidate principal component and the incidence of ADRs induced by nabumetone in Shanghai osteo-arthropathy patients. Method: A total of 145 patients were interviewed using the WHO-SF36 questionnaire for quality of life (QOL) assessment before the administration of nabumetone. The sub-items of the questionnaire were analyzed using PCA and several comprehensive variables were established. Relationships between these newly formed variables and the overall incidence of adverse drug reactions (ADRs) caused by nabumetone were evaluated using univariate and multivariate analyses. Results: Several principal components were identified and their linear parameters were estimated using PCA. Through univariate analysis, only 1 principal component – “adverse effect on work and daily activities as a result of emotional problems” – was found related to the incidence of ADRs. The odds ratio (OR) was 1.28 with 95% confidence intervals (CI) of 1.11 and 1.48, p = 0.0384. This result was validated using a multivariate logistic analysis performed on all the alternative candidate covariates, including family income, a history of ADRs on NSAIDs, the course of the disease, level of education, control of stress, coffee consumption and consumption of salty food. The covariate information was taken from other parts of the clinical report form (CRF) used in this research. The analysis proved that the principal component, adverse effect on work and daily activities as a result of emotional problems, was an independent factor related to the overall incidence of ADRs. The odds ratio (OR) from the logistic analysis was 1.34, with 95% confidence intervals (CI) of 1.16 and 1.55, p = 0.0309. Conclusions: The principal component identified can be applied to overcome some limitations in the WHO-SF36 questionnaire such as high correlation between variables, information overlaps and weak representation of variables and the statistical data analysis of QOL can therefore be made more effective. The study shows that the principal component “adverse effect on work and daily activities as a result of emotional problems” is an independent predictor of the overall incidence of ADRs induced by nabumetone.
Case report
High-dose exposure to valsartan with suicidal intention
Abstract
B. Kumbasar, F. Atlibatur Akbas, K. Serez, E. Ger, S. Uzunoglu, K. Ergen and M. Ayer
13rd Internal Medicine Clinic, and 24th Internal Medicine Clinic, Haseki Hospital, Istanbul, Turkey
Valsartan is a strong angiotensin receptor inhibitor specific for the angiotensin I receptor, which has been proven safe and well-tolerated in clinical trials. We were able to confirm its safety and tolerability in a case of high-dose exposure to valsartan with suicidal intention. A 25-year-old, fully conscious, female patient was brought to our hospital by relatives on July 24, 2001, at 9:15 p.m. following intake of a high dose of valsartan. It was established that she had taken 28 Diovan 80 mg tablets (2.24 g) 5 hours before admission to the hospital. Her clinical condition at the time of admission was good and did not deteriorate after admission. During the follow-up, her blood pressure never fell below 90/60 mmHg. The only complaint she had were painful muscle cramps which, with only supportive therapy, disappeared spontaneously over 2 days, and her blood pressure also returned to normal during this period. This report demonstrates the effect/side effect profile of valsartan when taken at a high dose, not achievable in a clinical trial.
Bioavailability section
Bioequivalence study of generic amlodipine in healthy Thai male volunteers
Abstract
N. Rojanasthien, S. Teekachunhatean, K. Jakob, M. Gaupp, P. Arnold, N. Chaichana and W. Martin
1Division of Clinical Pharmacology, Department of Pharmacology,
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, and
2The Pharmakin GmbH, Ulm, Germany
Subjects, material and methods: To determine the bioequivalence of 10 mg generic amlodipine in healthy male volunteers, the reference and the test formulations were administered as a single oral dose after overnight fasting in a crossover study separated by 2-week washout interval. After dosing, serial blood samples were collected for a period of 144 h. Plasma amlodipine concentrations were determined by LC-MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. Results: The mean elimination half-life (t1/2) for the test (40 h) and the reference (44 h) were within the values previously reported. The rate of absorption reflected by tmax had a difference of –0.33 h, with a 90% CI of (–1.52) – 0.85 (acceptable range ± 1.3). Although the tmax of the test (5 h) was faster than the reference (6 h), the mean (90% CI) of the AUC0-¥ and
Cmax ratios Test/References were 0.91 (0.87 – 0.97) and 1.01 (0.93 – 1.09), respectively. These values were within the range of 0.80 – 1.25, thus, the study demonstrated the bioequivalence of the 2 formulations.
Bioavailability section
Bioequivalence of 2 oral ciprofloxacin tablets formulations
Abstract
A. Cuadrado1,3, A.R. Gascón2,3, M.A. Solinís2,3, E. Ramírez1,3, R.M. Hernández2,3, U. Knie4 and J.L. Pedraz2,3
1Clinical Trial Unit of the Txagorritxu Hospital, Vitoria, Spain,
2Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria, Spain, 3Pharmaceutical Development Unit, Vitoria, Spain, and 4Department of Pharmaceutical Research and Development Dr. August Wolff GmbH, Bielefeld, Germany
The relative bioavailability of a new 750 mg tablet formulation of ciprofloxacin (test formulation supplied by Dr. August Wolff GmbH and Co., Germany) was compared with that of Ciprobay tablets 750 mg (reference formulation from Bayer Vital GmbH and Co., Germany). Twenty-four healthy volunteers (12 male and 12 female) were included in this single-dose, 2-sequence, crossover randomized study. Blood samples were obtained prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 30 hours after drug administration. Plasma concentrations of ciprofloxacin were determined by HPLC. No differences were found when the in vitro dissolution profiles of both for-mulations were compared. The pharmacokinetic parameters AUC0-t, AUC0-¥, Cmax and Cmax/AUC0-¥ were tested for bioequivalence after log-transformation of data, and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following mean values for the test/reference ratios (90% standard confidence intervals in parenthesis (ln-transformed data): 1.01 (0.95 – 1.07) for AUC0-t, 0.99 (0.93 – 1.05) for AUC0-¥, 1.05 (0.97 – 1.14) for Cmax and 1.06 (0.97 – 1.15) for Cmax/AUC0-¥. The nonparametric confidence interval for tmax was 0.77 – 1.15. All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80 – 1.25 limits; the 90% confidence interval for tmax slightly exceeded limits of bioequivalence. We conclude that both formulations show bioequivalence for both the rate and the extent of absorption.
Bioavailability section
A comparative clarithromycin bioavailability study: determination of clarithromycin and 14-(R)-hydroxyclarithromycin under fasting and fed conditions
Abstract
P. Benninger, A. Cooper, R. Moisan, P. Patel, A. Elvin and J.J. Thiessen
1Allied Clinical Research, Mississauga, Canada, and
2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
Objective: To report the first comprehensive analysis of clarithromycin (CLA) and 14-(R)-hydroxyclarithromcin (14R) bioequivalence metrics under both fasting and fed conditions when using a validated analytical method. Methods and materials: In separate, single dose bioequivalence studies, fasting (n = 40) and fed (n = 18) non-smoking subjects entered a 2-treatment, 2-period, 2-sequence, crossover trial to assess the comparative bioavailability of a 500 mg generic clarithromycin tablet (IVAX Pharmaceuticals, NJ, USA) relative to the reference product (Biaxin® Filmtab, Abbott Laboratories, IL, USA). The validated assay employed an HPLC coupled to a triple stage quadrupole mass spectrometer. Results: The analytics permitted plasma samples to be measured for both analytes with high precision and a lower limit of quantitation (LLOQ) of 11 ng/ml. In both fasting and fed studies, and for both analytes, the IVAX product met the common mean geometric ratio and 90% confidence limits in order to be declared bioequivalent with Biaxin Filmtab. Furthermore, the intra-subject variabilities for the comparative AUC metrics in both studies and for both analytes were £ 21% and £ 26% for Cmax. Conclusions: The fasting and fed results present definitive evidence that 500 mg IVAX clarithromycin and Biaxin® Filmtab are bioequivalent under both fasting and fed conditions, whether based on CLA or 14R. Furthermore, at a 500 mg dose, clarithromycin is not a highly variable drug.
Letter to the Editor
Pulmonary edema due to ritodrine
Abstract
N. Kayacan, L. Dosemeci, G. Arici, B. Karsli and M. Erman
Letter to the Editor
Announcements
