Volume 41, No. 6/2003(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Viewpoint
Pharmacogenomics and drug response
M. Müller
Abstract
M. Müller
Department of Clinical Pharmacology, Vienna General Hospital, Vienna University School of Medicine, Vienna, Austria
Following pioneer work in the early 20th century, the era of molecular pharmacogenomics started with the cloning of a polymorphic gene encoding the drug-metabolizing enzyme cytochrome P450-2D6. Today, recent conceptual and methodological advances in genomics allow a much broader approach to elucidating inheritance patterns in drug response and identification of functional polymorphisms, that affect drug response, has become a key issue. Despite recent euphoria about potential applications of pharmacogenomic principles, currently available pharmacogenomic data have had modest overall impact on the routine of drug therapy. Most data were derived from single gene approaches for select drug metabolizing enzymes with extreme phenotypes. Data on genetic determinants of drug distribution, absorption and response, however, are scarce and it seems that most events in the dose-response cascade follow a complex interplay of environmental factors with several genes encoding proteins in multiple pathways. Thus, there is great need for clinical studies on genotype-phenotype and gene environment interactions, based on multiple gene approaches. Major challenges also relate to practical aspects of clinical pharmacogenomic studies, e.g. appropriate data handling, selection of appropriate study designs and control groups and issues of prediction accuracy. To move to a clinically useful and predictive level in pharmacogenomics, much work remains to be completed. Nevertheless, it can be anticipated that for select drugs, pharmacogenomics may lead to a shift from the current strategy of developing medications for a statistically optimized fraction of patients to a strategy that aims to provide tailored medications for genetically diverse patients.
Pharmacodynamics
Effects of fenofibrate and simvastatin on plasma sICAM-1 and MCP-1 concentrations in patients
with hyperlipoproteinemia
J. Kowalski, B. Okopien, A. Madej, M. Zielinski, D. Belowski, Z. Kalina and Z.S. Herman
Abstract
J. Kowalski, B. Okopien, A. Madej, M. Zielinski, D. Belowski, Z. Kalina and Z.S. Herman
1Department of Clinical Pharmacology, Medical University of Silesia, and 2Department of Internal Diseases and Clinical Pharmacology,
Medical University of Silesia, Katowice, Poland
Objective: The most important mechanism through which high plasma lipid levels trigger the formation of atherosclerotic lesions involves a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate an extralipid effect of fenofibrate and simvastatin by examination of MCP-1 and ICAM-1 plasma concentration after 1-month hypolipemic therapy as well as MCP-1 and ICAM-1 plasma concentration after 1-month therapy with low-fat diet alone. Methods: Twenty patients with HLPIIb or HLPIIa, who did not respond to a low-fat diet, were treated with micronized fenofibrate or simvastatin, respectively, for 1 month. The control group included 18 normo-lipidemic, healthy age-matched participants; 10 patients with HLPIIa were effectively treated with a low-fat diet for 1 month. This group was compared to a control group of 10 healthy subjects. The plasma adhesion molecule levels were measured by an ELISA method before and after the treatment. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. Results: sICAM-1 levels were significantly higher in HLPIIa and HLPIIb patients (331 ± 19 ng/ml and 423 ± 23 ng/ml, respectively) compared with the control group (236 ± 12 mg/ml). MCP-1 levels were also significantly higher in HLPIIa and HLPIIb patients (170 ± 9 pg/ml and 183 ± 15 pg/ml, respectively) compared with the control group (100 ± 4 pg/ml). Fenofibrate (200 mg daily) significantly decreased sICAM-1 (by 17%) and MCP-1 levels (by 12.5%). Simvastatin (20 mg daily) caused a significant decrease (by 10.5%) in sICAM-1 levels only. Restriction in dietary lipids resulted in a significant decrease in the levels of cholesterol (8%), LDL cholesterol (14.9%) and ApoB (12.7%), which was accompanied by a significant decrease in the levels of sICAM-1 (8.7%) and MCP-1 (16.1%). Conclusion: The results of this study suggest that high lipid levels are accompanied by increased levels of sICAM-1 and MCP-1 and that hypolipidemic therapy only slightly decreases the levels of these molecules compared with plasma lipids. The hypolipidemic diet-related decrease in the levels of lipids, ICAM-1 and MCP-1 suggests that it is a drug-induced decrease in lipid levels but not a direct action of the drugs on endothelial cells, smooth muscle cells or macrophages that leads to a decrease in the levels of adhesion molecules.
Pharmacodynamics
Receptor assay based on surface plasmon resonance for the assessment of the complex formation activity of cyclosporin A and its metabolites
B. Vollenbroeker, M. Fobker, B. Specht, N. Bartetzko, M. Erren, F. Spener and H. Hohage
Abstract
B. Vollenbroeker1,4, M. Fobker2, B. Specht3, N. Bartetzko3, M. Erren2, F. Spener4 and H. Hohage1
1Medizinische Klinik und Poliklinik D, 2Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Münster, 3Inventus BioTec, Gesellschaft für innovative Bioanalytik, Biosensoren und Diagnostika mbH und Co. KG, Münster, und 4Institut für Biochemie, Universität Münster, Germany
Objective: A new automated receptor assay has been used to determine the complex formation activity of cyclosporin A (CsA) and its metabolites in whole blood. Methods: CsA in vivo forms a complex with cyclophilin A and calcineurin leading to an inhibition of the calmodulin-dependent phosphatase activity of calcineurin. The equilibrium complex formation gives information about the potential immunosuppressive activity of CsA and its metabolites. To measure the amount of this complex the authors developed an automated receptor assay based on an optical biosensor (Biacore) with surface plasmon resonance (SPR) technology. Results: In the range of 50 – 300 nM CsA, the intra-day coefficient of variation (CV) was 7.2%, and the inter-day CV was 10.1%. Measuring range of the assay was 10 – 500 nM with a detection limit of 5 nM and a processing time of 10 min. Recovery rate for sample pretreatment was 74 ± 5%. 193 blood specimens from heart transplant recipients were analyzed with 3 different methods. The results determined with the receptor assay were correlated with those obtained by fluorescence polarization immunoassay (FPIA; r = 0.599) and high-performance liquid chromatography (HPLC; r = 0.615). Conclusion: The receptor assay determines the complex formation activity of CsA and its metabolites with high sensitivity and precision.
Pharmacokinetics
Effect of severe renal
impairment on the pharmacokinetics and tolerability of the parenteral endothelin antagonist tezosentan
P.L.M. van Giersbergen and J. Dingemanse
Abstract
P.L.M. van Giersbergen and J. Dingemanse
Actelion Pharmaceuticals Ltd., Clinical Pharmacology,
Allschwil, Switzerland
Background: Tezosentan, an endothelin receptor antagonist, is under development for the treatment of acute heart failure. Impaired renal function is a frequent comorbidity in these patients. Objective: To assess the pharmacokinetics and tolerability of tezosentan in 8 patients with severe renal impairment (creatinine clearance < 30 ml/min) compared to 8 healthy subjects. Methods: Tezosentan was infused at a rate of 100 mg/h for 1 h. Blood and urine samples were collected for pharmacokinetic determinations. Vital signs, ECG, adverse events and clinical laboratory parameters were monitored to assess tolerability. Results: The mean (95% confidence interval) volume of distribution and clearance of tezosentan in renal patients were 15 (13, 18) l and 42 (34, 52) l/h, respectively, and did not differ significantly from the values of 18 (15, 20) l and 36 (29, 44) l/h found in healthy subjects. In patients, the renal excretion of tezosentan was impaired. Tezosentan caused a decrease in blood pressure and was well tolerated in both groups. Conclusion: No clinically relevant effects of severe renal impairment on the pharmacokinetics and tolerability of tezosentan were found. Therefore, no dose adjustment of tezosentan is deemed necessary in patients with any grade of renal impairment.
Pharmacokinetics
Pharmacokinetics and tissue penetration of pefloxacin plus metronidazole after administration as surgical prophylaxis in colorectal surgery
A.R. Gascón, G. Gutiérrez-Aragón, R.M. Hernández, J. Errasti and J.L. Pedraz
Abstract
A.R. Gascón1, G. Gutiérrez-Aragón2, R.M. Hernández1, J. Errasti2 and J.L. Pedraz1
1Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria, and
2General Surgery Department, Txagorritxu Hospital, Vitoria, Spain
The levels of metronidazole and pefloxacin in plasma and tissue penetration of both drugs were studied after prophylactic administration to 7 patients undergoing colorectal surgery. Metronidazole (1,500 mg) and pefloxacin (800 mg) were administered as an intravenous infusion 1 hour before surgery. Mean plasma levels of pefloxacin decreased from 12.92 ± 4.10 mg/ml at the end of the infusion to 2.18 ± 1.03 mg/ml at 36 h. These values were above the MIC90 for E. coli (0.125 mg/ml) and E. faecalis (0.5 mg/ml), microorganisms responsible for abdominal infections. Tissue pefloxacin levels were also measured with a range from 0.72 – 7.78 mg/g in subcutaneous cell tissue, from 1.94 – 17.55 mg/g in peritoneum and from 2.76 – 21.99 mg/g in colon wall. Mean plasma concentrations of metronidazole decreased from 39.89 ± 17.08 mg/ml at the end of the infusion to 2.63 ± 1.11 mg/ml at 36 h. During this period, concentrations were higher than 2 mg/ml, the MIC90 value for B. fragilis, the anaerobic pathogen more frequently involved in postoperative infections after rectal and colonic surgery. Tissue metronidazole levels ranged from 3.64 – 13.37 mg/g in subcutaneous cell tissue, from 3.26 – 41.66 mg/g in peritoneum and from 6.72 – 43.12 mg/g in colon wall. The AUC/MIC values (efficacy parameter for concentration-dependent killing antibiotics such as pefloxacin and metronidazole) obtained were the following: metronidazole AUC/MIC value for B. fragilis was 173; pefloxacin AUC/MIC values for E. coli and E. faecalis were 941 and 235, respectively. The values of these parameters are higher than the recommended values to ensure efficacy, which means good exposure of the antimicrobials to the microorganisms. In conclusion, the combination of pefloxacin and metronidazole as prophylactic agents to prevent infections in patients undergoing colorectal surgery produce plasma and tissue levels above the MIC values of the main pathogens responsible for this kind of infections.
Letter to the Editor and Reply
Letter referring to the publication of Joshi et al. – Int. J. of Clinical Pharmacology and Therapeutics, Vol. 41 – No. 1/2003 (42-48)
R.K. Chopra
Letter to the Editor and Reply
Reply
A.D. Halpner
