Volume 38, No. 11/2000(November)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Obituary / Dr. phil. Karl Feistle
G. Hitzenberger
Original
Drug-drug interactions in medical patients: Effects of in-hospital treatment and relation to multiple drug use
G.I. Köhler, S.M. Bode-Böger, R. Busse, M. Hoopmann, T. Welte and R.H. Böger
Abstract
G.I. Köhler1, S.M. Bode-Böger1, R. Busse2, M. Hoopmann2, T. Welte3 and R.H. Böger1
1Institute of Clinical Pharmacology, 2Department of Epidemiology, Social Medicine and Health System Research, Medical School, Hannover, and 3Department of Pneumology, Otto von Guericke University, Magdeburg, Germany
Objectives: Adverse drug reactions (ADRs) are a major cause of hospital admissions, thereby leading to significant medical and economical problems. Drug interactions contribute to a major part of ADRs, especially in elderly patients and in patients under polymedication. As a peculiarity of the German health care system the general practitioner is less involved in patient care during hospital stay than in other countries. Consequently, changes in medication at the transition point from out-patient to in-patient care and back may contribute to drug-related problems. Patients: In the present study we investigated potential interactions in 169 consecutive patients with the diagnosis CHD (coronary heart disease) or COLD (chronic obstructive lung disease) who were admitted to the University Hospitals of Hannover and Magdeburg. Methods: For each patient, potential interactions between prescribed drugs at admission, at discharge, and 3 months after discharge were assessed by using drug interaction data bases. Results: We found that the number of drugs taken per patient as well as the number of interactions per patient are higher during hospitalization than before admission (pre-admission), and fall back after the hospital stay (post-discharge), but not to the pre-admission level. The number of potential interactions was significantly correlated in a polynomial manner to the number of drugs taken by each patient. The number of patients without a potential interaction was 44.4% pre-admission, 39.6% at discharge, and 39.1% post-discharge. Patients with potential interactions had a mean of 2.8, 2.7, and 2.4 interactions at each of the time points. Drug classes mainly involved with potential interactions were kaliuretic diuretics (recorded by 43.3% at discharge), ACE inhibitors (30.3%), anticoagulants and aggregation inhibitors (20.4%) and digitalis glycosides (14.7%). Regarding the frequency of the interaction categories, 68 – 70% of the potential interactions demand clinical attention, while 1 – 2% are life-threatening. 17 – 19% may result in therapeutic benefit; 10 – 12% are without clinical relevance. Conclusions: The risk of drug interactions increases exponentially with the number of drugs given to a patient. Although we have no data on the fraction of interactions that became clinically manifest, our study indicates that prescribing fewer drugs can reduce the risk of suffering from sickness secondary to drug interactions. Taking this risk into account may help to improve the quality of drug treatment and to save costs.Correspondence to:
Dr. R.H. Böger; Clinical Pharmacology, Department of Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany
Original
Liver and gut mucosa acetylation of mesalazine in healthy volunteers
T.B. Vree, E. Dammers, P.S. Exler, F. Sörgel, S. Bondesen and R.A.A. Maes
Abstract
T.B. Vree1, E. Dammers2, P.S. Exler3, F. Sörgel4, S. Bondesen5 and R.A.A. Maes6
1Institute for Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, 2DADA Consultancy, Nijmegen, 3Disphar International, Hengelo (Gld), The Netherlands, 4Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany, 5Frederiksberg Hospital, Copenhagen, Denmark, and 6Department of Human Toxicology, University of Utrecht, Utrecht, The Netherlands
Aim: The aim of this investigation was to identify which part of a dose mesalazine is acetylated by enzymes in the gut wall during the absorption process, and which part by the liver enzymes after absorption. Method: This study was based on data from four bioequivalence studies of different formulations of tablets (gastro-resistant single dose 500 mg (n = 24) and prolonged-release tablets (single dose 1000 mg, n = 18; multiple dose 1000 mg t.i.d. six days n = 28), suppositories (single 500 mg dose, n = 24) and a study with two i.v. administrations of 100 and 250 mg mesalazine (n = 6). In total, 200 administrations were carried out and plasma concentration-time curves obtained and analyzed. There was a large variability in the absorption of mesalazine for all formulations. The plasma concentration-time curves of parent drug and metabolite acetylmesalazine run nearly parallel, independent of the formulation and the dose. Plasma and urine mesalazine and acetylmesalazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass-spectrometric detection. Results: As a result of the large variations in release and absorption of mesalazine in the pharmaceutical formulations and administrations, it was possible to demonstrate that acetylation occurs in the gut wall and in the liver. By comparing oral and rectal data to intravenous data, it was possible to indicate where (and to what extent) acetylation occurs in the gut wall, in the liver, or both. Rectal administration of a mesalazine suppository and intravenous administration results in hepatic acetylation. Oral administrations of mesalazine results in both gut wall and hepatic acetylation. Acetylation by the gut wall amounts to 30% of the dose for gastro-resistant tablets and to 40% of the dose for prolonged-release tablets.Correspondence to:
Dr. T.B. Vree; Institute for Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands
Original
Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects
U. Ebert, R. Oertel and W. Kirch
Abstract
U. Ebert, R. Oertel and W. Kirch
Institute of Clinical Pharmacology, Faculty of Medicine, University of Technology, Dresden, Germany
Objectives: To investigate the effects of grapefruit juice on absolute bioavailability of scopolamine in healthy subjects and to evaluate differences in pharmacokinetics and pharmacodynamics between genders. Subjects, material and methods: 14 healthy subjects (7 men and 7 women) received scopolamine 0.5 mg as intravenous infusion, and as oral ingestion with and without grapefruit juice on separate occasions. Serum and urine samples were analyzed using gaschromatography-ion trap tandem mass spectrometry. Changes in subjective state were determined up to 24 hours after drug administration. Results: After oral administration, pretreatment with grapefruit juice led to a 30% increase in systemic bioavailability of scopolamine (p = 0.005) and a significant increase in time to reach peak serum concentration (tmax) of scopolamine (p < 0.001). The Cmax value (6.61 ± 0.63 ng/ml) of scopolamine after i.v. administration in male subjects was significant higher compared with the value in female subjects (3.93 ± 0.04 ng/ml; geometric mean ± SEM; p = 0.007). No differences were found in urinary excretion rate of scopolamine and scopolamine glucuronide across genders and between the three different routes of scopolamine administration. Scopolamine produced time-dependent decrements in subjective alertness while contentment and calmness were not influenced. Conclusions: Pretreatment with grapefruit juice delayed the absorption and increased the bioavailability of scopolamine, whereas elimination was not significantly affected. This study identified an influence of gender on Cmax of scopolamine after i.v. infusion.Correspondence to:
Dr. U. Ebert; Institut für Klinische Pharmakologie, Fakultät für Medizin, Technische Universität Dresden, Fiedlerstraße 27, D-01307 Dresden, Germany
Original
Similarity in the linear and non-linear oral absorption of drugs between human and rat
W.L. Chiou, C. Ma, S.M. Chung, T.C. Wu and H.Y. Jeong
Abstract
W.L. Chiou, C. Ma, S.M. Chung, T.C. Wu and H.Y. Jeong
Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, USA
Objective: The main aim of this study was to provide a simple, pharmacokinetic rationale for great similarity in the extent (Fab) of gastrointestinal absorption of about 100 different, diverse compounds between human and the rat in linear dosing range, and to test the general applicability of a novel empirical method to correlate the non-linear Fab between the human and the rat by normalizing doses by body surface area (BSA) or body weight0.67. Method: The mean small intestinal transit time (t) of 36 rats was estimated from the reported study, and this was used to compare with that in humans. The reported great similarity in apparent first-order absorption rate constants (k) of seven structurally diverse compounds between the two species were obtained. Extensive computer search was made and non-linear Fab data for the two species were obtained for chlorothiazide, acyclovir, miglitol and pafenolol. Results: The mean t for rats was estimated to be 3.32 h which is almost identical to that reported in humans. The great similarity in Fab between human and rat in linear absorption range can be rationalized by similar t and k between the two species. The markedly different Fab vs dose/kg of body weight profiles between human and rat for the four drugs showing dose-dependent Fab were found to collapse when doses were normalized by BW0.67. Conclusion: For Fab not limited by the solubility problem, the great similarity in Fab between human and rat in linear absorption range can be rationalized by the similar t and k. For non-linear Fab drugs, great similarity in Fab can also be obtained between human and rat when doses are normalized by BSA or BW0.67. Regardless of absorption properties (active, passive or facilitated), similar Fab between the two species may be generally obtained when doses used in humans are about 5 to 7 times lower than that in rats. The above findings may be valuable in drug development.Correspondence to:
Prof. Dr. W.L. Chiou; Department of Pharmaceutics and Pharmacodynamics (M/C 865), University of Illinois at Chicago, 833 South Wood, Chicago, IL 60612, USA
Original
Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine
K. Malminiemi, T. Keränen, T. Kerttula, E. Moilanen and P. Ylitalo
Abstract
K. Malminiemi1, T. Keränen2, T. Kerttula1, E. Moilanen2 and P. Ylitalo2
1Department of Clinical Chemistry, Tampere University Hospital, and 2Department of Pharmacological Sciences, University of Tampere, Tampere, Finland
Aim and method: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. Results: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (± SEM) elimination half-life of CBZ was 33.0 ± 1.8 h after pretreatment with placebo and 30.1 ± 2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638 ± 45 mmol/l after placebo and 624 ± 53 mmol/l after LTG (NS). Changes in the peak serum concentration, from 9.0 ± 0.3 mmol/l to 9.2 ± 0.4 mmol/l (LTG), and in the time to peak serum concentration, from 9.3 ± 1.1 h to 9.1 ± 1.2 h (LTG), were also not significant. Conclusion: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.Correspondence to:
Dr. K. Malminiemi; TaUH, Department of Clinical Chemistry, POB 2000, Tampere, FIN-33521 Finland
Original
Bioavailability of a new effervescent tablet of diclofenac
B. Terhaag, A. Hoffmann, M. Barkworth and B. Vens-Cappell
Abstract
B. Terhaag1, A. Hoffmann1, M. Barkworth2 and B. Vens-Cappell2
1Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Radebeul, and 2Phoenix International McKnight, Hamburg,Germany
Objective: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). Subjects and method: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-¥ and Cmax. Results: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean ± SD) for DIC-effervesc is 950 ± 341 ng/ml (first Cmax) and for DIC-enteric 1364 ± 335 ng/ml. The mean AUC0-¥ (arithm. mean ± SD) amounts to 1097 ± 210 ng/ml´h for DIC-effervesc and 1262 ± 220 ng/ml´h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 – 91.3%). DIC-effervesc was well tolerated. Conclusion: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragée. A rapid onset of therapeutic effect is postulated in acute pain disorders.Correspondence to:
Prof. Dr. B. Terhaag; Arzneimittelwerk Dresden GmbH, Department of Medical Research, Meißner Straße 35, D-01445 Radebeul, Germany
