Volume 39, No. 2/2001(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Message from the Editor-in-Chief, Gerhart Hitzenberger and the Editor-in-Chief Elect Barry G. Woodcock
G. Hitzenberger und B.G. Woodcock
Abstract
G. Hitzenberger und B.G. Woodcock
Immun system
Levels of sICAM-1, sVCAM-1 and MCP-1 in patients with hyperlipoproteinemia IIa and -IIb
J. Kowalski, B. Okopien, A. Madej, K. Makowiecka, M. Zielinski, Z. Kalina and Z.S. Herman
Abstract
J. Kowalski1, B. Okopien1, A. Madej1, K. Makowiecka1, M. Zielinski1, Z. Kalina2 and Z.S. Herman1
1Department of Clinical Pharmacology, and 2Department of Internal Diseases, Medical University of Silesia, Katowice, Poland
Objective: Hyperlipoproteinemia is one of the factors that are involved in the development of atherosclerosis. One of the mechanisms through which these high plasma lipid levels trigger the formation of atherosclerotic lesions is a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate the plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in patients with Type IIa (HLP-IIa) and IIb (HLP-IIb) hyperlipoproteinemias. Subjects: Twenty patients with HLP-IIa, 20 patients with HLP-IIb and 23 control subjects were studied. To accurately evaluate adhesion molecule levels, we excluded those hyperlipemic patients and control subjects who had an inflammatory disease. Methods: Plasma sICAM-1, sVCAM-1 and MCP-1 levels were measured by the ELISA method. Results: sVCAM-1 levels in HLP-IIa and HLP-IIb patients (535 ± 27 ng/ml and 545 ± 22 ng/ml, respectively) did not differ significantly from those in the control group (558 ± 20 ng/ml). sICAM-1 levels were significantly higher in patients with HLP-IIa and HLP-IIb (279 ± 10 ng/ml and 322 ± 12 ng/ml, respectively) compared to the control group (226 ± 10 ng/ml). MCP-1 levels were significantly higher in HLP-IIa and HLP-IIb patients (151 ± 12 pg/ml vs 154 ± 12 pg/ml, respectively) compared to healthy controls (98 ± 4 pg/ml). sICAM-1 levels in the HLP-IIb group were significantly higher than in the HLP-IIa group. Conclusion: The results of the study suggest that lipid abnormalities affect the levels of adhesion molecules and chemokines in plasma.Correspondence to:
Prof. Dr. Z.S. Herman; Department of Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
Metabolism
Caffeine metabolism before and after liver transplantation
Y.C. Bechtel, H. Lelouët, S. Hrusovsky, M.P. Brientini, G. Mantion, G. Paintaud, J.P. Miguet and P.R. Bechtel
Abstract
Y.C. Bechtel1, H. Lelouët1, S. Hrusovsky3, M.P. Brientini1, G. Mantion2, G. Paintaud4, J.P. Miguet3 and P.R. Bechtel1
1Département de Pharmacologie Clinique, Faculté de Médecine, 2Service de Chirurgie Digestive et Vasculaire, Hôpital Universitaire, 3Service d’Hépatologie, Hôpital Universitaire, Besançon, and 4Service de Pharmacologie, Hôpital Universitaire, Tours, France
Aim: To study drug metabolism in patients before and after liver transplantation using caffeine as a probe drug. Forty-five patients undergoing liver transplantation for various liver diseases and who had well documented dossiers were selected for the study. Before the liver transplantation and 1 month, 1 year, and 6 years after liver transplantation, they were given 200 mg of caffeine by the oral route in the morning after voiding their bladder. Twenty-four-hour urine samples were collected and caffeine and metabolites were determined by HPLC: 1-methylurate (1U), 1-methylxanthine (1X), 1.7-dimethylurate (17U), 1.7-dimethylxanthine (17X), 7-methylxanthine (7X), 3-methylxanthine (3X), 1.3-dimethylurate (13U), 3.7-dimethylxanthine (37X), 1.3-dimethylxanthine (13X), 1.3.7-trimethylxanthine = caffeine (137X). Indices of enzyme activities were calculated from the following urinary elimination ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/ 17X for CYP2A6, 1U/1X for xanthine oxidase (XO), AFMU/(AFMU+ 1U+1X) for N-acetyltransferase (NAT-2). Results: Compared with results obtained in a group of 70 healthy subjects, caffeine metabolism before liver transplantation was deeply depressed with a decreased elimination rate in the case of all metabolites and a decreased CYP1A2 activity. Caffeine metabolism began to return to the control values one month after transplantation. One year and 6 years after liver transplantation, quantitatively, the metabolism of caffeine was stable and not different from control, but with qualitative modifications. CYP1A2 activity was decreased with reduced urinary elimination rates of 1X and 17X. XO and CYP2A6 activities and 1U and 17U urinary elimination rates were increased. Immunosuppressive treatment was possibly responsible for the metabolic pathway changes. Almost the same modifications were observed in 9 patients after bone marrow transplantation who had been treated with the same immunosuppressive drugs, cyclosporine and azathioprine. During severe rejection phases in 6 of the liver transplant patients, caffeine metabolism was progressively decreased when the usual liver function tests showed moderate but uniform changes. Conclusion: Despite an apparent normal drug-metabolic function, immunosuppressive treatment induces stable variations in drug-metabolic pathways after liver transplantation which can be detected from the changes in caffeine metabolism.Correspondence to:
Prof. Dr. P.R. Bechtel; Faculté de Médecine, Place Saint Jacques, F-25030 Besançon Cedex, France
Email: yp.bechtel@freesbee.fr
Pharmacokinetics
Pharmacokinetics of oral talinolol following a single dose and during steady state in patients with chronic renal failure and healthy volunteers
M. Krueger, H. Achenbach, B. Terhaag, H. Haase, K. Richter, R. Oertel and R. Preiss
Abstract
M. Krueger1, H. Achenbach2, B. Terhaag3, H. Haase3, K. Richter4, R. Oertel4 and R. Preiss1
1Institute of Clinical Pharmacology, University of Leipzig, 2Department of Nephrology, University of Leipzig, 3Arzneimittelwerk Dresden GmbH, ASTA MEDICA AG and 4Institute of Clinical Pharmacology, Faculty of Medicine, University of Technology, Dresden, Germany
Objective: The objective of this study was to investigate the effect of renal impairment on the pharmacokinetics of the selective b1-receptor antagonist talinolol. Methods: Pharmacokinetic data were obtained in 12 healthy volunteers, 12 patients with renal impairment and 8 patients with terminal renal insufficiency after the oral administration of 100 mg talinolol and under steady state conditions (100 mg talinolol daily). Concentrations of talinolol in plasma, urine and dialysate during hemodialysis were measured with a validated HPLC-method. Results: Talinolol is absorbed quite rapidly from the gastrointestinal tract (tmax 2.5 – 4 h). Steady state conditions were reached within 3 – 4 days depending on renal function. The calculated mean elimination half-life (t1/2z) in healthy volunteers (11 male, 1 female) was about 12 h. After an oral dose of 100 mg, about 55% of the bioavailable talinolol is eliminated unchanged in the urine. This fraction is reduced to 25% in patients with moderate to severe renal failure. A strong correlation was found between the renal elimination of talinolol and creatinine clearance. In patients with renal failure, the delayed elimination leads to an increase in t1/2z and to a decrease in the apparent total body clearance. Steady state trough levels in these patients are about 2.2-fold higher than in volunteers. The hemodialysability of talinolol was low. Conclusion: The disposition of talinolol shows a strong dependence on the renal function. On the basis of the kinetic data for talinolol, dose reductions of 30 – 50% are recommended in subjects with moderate to severe renal impairment.Correspondence to:
Prof. Dr. R. Preiss; Institute of Clinical Pharmacology, University of Leipzig, Haertelstr. 16 – 18, 04107 Leipzig, Germany
Email: preir@medizin.uni-leipzig.de
Pharmacokinetics
Plasma and urine pharmacokinetics of the dopamine agonist a-dihydroergocryptine in patients with hepatic dysfunction
M. Althaus, C. de Mey, E. Ezan, I. Ciecko-Michalska, E. Kostka-Trabka, A. Goszcz and A. Retzow
Abstract
M. Althaus1, C. de Mey2, E. Ezan3, I. Ciecko-Michalska4, E. Kostka-Trabka5, A. Goszcz5 and A. Retzow6
1Desitin Arzneimittel GmbH, Hamburg, 2ACPS, Mainz-Kastel, Germany, 3CEA, Service de Pharmacologie et d’Immunologie, Gif-sur-Yvette, France, 4Clinic of Gastroenterology, 5Clinical Pharmacology, Collegium Medicum Jagellonian University, Kraków, Poland, and 6Paul-von-Schönaichstraße, Reinfeld, Germany
Objective: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged a-dihydroergocryptine (DHEC, AlmiridÒ, Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and urine in patients with impaired hepatic function, following administration of single oral doses. Methods: The study was carried out according to an open, uncontrolled, parallel-group design, investigating two study groups: patients with hepatic dysfunction, i.e. with evidence of stable cirrhosis (n = 10) and age- and sex-matched healthy subjects (n = 8). Each subject received a single dose of 20 mg DHEC. Blood samples were taken at specified intervals up to 72 h after dosing and urine was collected fractionally for 24 h. Concentrations of unchanged DHEC were determined by RIA and concentrations of total DHEC (unchanged and pooled metabolites) by EIA. Results: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by large variability. In patients with impaired hepatic function, the geometric mean Cmax and AUC0-¥ values for unchanged DHEC were 571.3 pg/ml (CV: 0.87) and 4038 pg×h/ml (CV: 1.04) and were approximately 2 times (2.04, 95% CI: 0.93 to 4.46 and 2.11, 95% CI: 0.58 to 7.73 for Cmax and AUC0-¥, respectively) larger than those measured in age-matched healthy controls. The 24-hour urinary excretion was approximately 3 times (3.41, 95% CI: 0.95 to 12.21) higher in patients with hepatic dysfunction. Similar results were obtained for total DHEC. Conclusions: The results reflect an increased systemic exposure in patients with impaired hepatic function which is not due to a reduced urinary excretion/elimination or reduced renal clearance. The most likely mechanism involved is a reduction in pre-systemic biotransformation. The observed range of effects on the pharmacokinetics of DHEC in patients with compromized hepatic function does not suggest the need to revise the dosage recommendations, since treatment with DHEC is generally started with low doses and is slowly up-titrated according to the individual response and the occurrence of adverse effects. Nevertheless, lower maintenance doses are likely to be achieved.Correspondence to:
Dr. M. Althaus; Desitin Arzneimittel GmbH, Weg beim Jäger 214, D-22335 Hamburg, Germany
Email: althaus@desitin.de
Drug disposition
Bioequivalence study of a novel Solutabâ tablet formulation of amoxicillin/clavulanic acid versus the originator film-coated tablet
H. Sourgens, H. Steinbrede, J.S.C. Verschoor, M.A. Bertola and B. Rayer
Abstract
H. Sourgens1, H. Steinbrede2, J.S.C. Verschoor3, M.A. Bertola3 and B. Rayer4
1University of Münster, 2Focus Clinical Drug Development GmbH, Neuss, 3Yamanouchi Europe B.V., Leiderdorp, The Netherlands, and 4Dr. Jung Gruppe, Medical Department, Planegg, Germany
With amoxicillin/clavulanic acid Solutab tablet, a new tablet formulation of amoxicillin/clavulanic acid (500/125), was developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation, taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentanâ film-coated tablet. The study was performed in 48 healthy volunteers, according to an open, single-dose three-period, crossover design. Blood samples were taken prior to each administration and at 10 time points after dosing. Plasma concentrations of amoxicillin and clavulanic acid were determined by validated high performance liquid chromatography with UV detection. With regard to amoxicillin, the results were within the preset bioequivalence range of 0.8 to 1.25 for the ratios of the primary parameters AUC(0-t) and Cmax. In terms of clavulanic acid the 90% confidence intervals of the ratios for AUC(0-t) and Cmax versus the reference lay outside the predefined bioequivalence range of 0.75 to 1.33. This result, however, was mainly due to the large variability of the reference formulation compared to the amoxicillin/clavulanic acid SolutabÒ tablet. Based on statistical indications that 3/48 subjects with extremely low levels on the reference formulation could be regarded as “outliers” and after excluding these subjects’ data from the statistical analysis, results for clavulanic acid were within the predefined bioequivalence range of 0.75 to 1.33. Overall, the amoxicillin/clavulanic acid SolutabÒ tablet provided, in comparison to the reference tablet, less variable levels of clavulanic acid, thus giving more appropriate protection to the available amoxicillin. Thirteen adverse events were reported post dosing by 7 subjects. There were no differences in incidence of adverse events between amoxicillin/clavulanic acid SolutabÒ tablet taken intact or dispersed and Augmentanâ.Correspondence to:
Dr. M.A. Bertola, Yamanouchi Europe B.V., PO Box 108, Elisabethof 1, NL-2350 AC Leiderdorp, The Netherlands
Drug disposition
Bioequivalence of two aceclofenac tablet formulations after a single oral dose to healthy male Korean volunteers
Y.G. Kim, Y.J. Lee, H.J. Kim, S.D. Lee, J.W. Kwon, W.B. Kim, C.-K. Shim and M.G. Lee
Abstract
Y.G. Kim1, Y.J. Lee1, H.J. Kim2, S.D. Lee2, J.W. Kwon2, W.B. Kim2, C.-K. Shim1 and M.G. Lee1
1College of Pharmacy, Seoul National University, and 2Research Laboratory, Dong-A Pharmaceutical Company, Yongin, Korea
A bioequivalence study of aceclofenac tablets (test formulation: Dong-A, reference formulation: Airtal) was conducted in 16 healthy male Korean volunteers who received each medicine at a dose of 100 mg in a 2 × 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of aceclofenac were monitored by high-performance liquid chromatography over a period of 24 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and nontransformed tmax. There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 1.04 (0.93 ~ 1.17) and 0.99 (0.91 ~ 1.08), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value for tmax was 0.75 (0.00 ~ 1.00). Moreover, the modified Pitman-Morgan’s adjusted F-test indicated that the bioavailabilities of aceclofenac in the 2 medications were comparable regarding intra- and interindividual variability. Therefore, these results indicate that the 2 medications of aceclofenac are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
1College of Pharmacy, Seoul National University, and 2Research Laboratory, Dong-A Pharmaceutical Company, Yongin, Korea
Abstracts
The 14th Symposium of the “Working Group for Pharmacology in Oncology and Hematology (APOH)”
