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Abstract

M. Zaigler, I. Tantcheva-Poór and U. Fuhr

Clinical Pharmacology, Institute of Pharmacology, University of Köln, Germany
Pronounced interindividual differences in drug disposition are mainly caused by differences in the activity of liver drug-metabolizing enzymes. These depend on known and unknown covariates, including genetic as well as environmental factors. Phenotyping, i.e. assessment of enzyme activities in vivo after administration of a test dose, seems to be a promising tool for determining actual metabolic capacities. Although it is a well-established experimental approach, phenotyping has not yet found its way into clinical practice. Main reasons for this are lack of validation for many probes and assays used, complicated procedures, invasiveness, semi-quantitative test results, non-compliance on behalf of the subjects tested, high costs, and lack of prospective clinical studies to assess the benefit of phenotyping for patients. Problems and perspectives of phenotyping are exemplified for the cytochrome P-450 enzymes CYP1A2 and CYP3A4, two major human drug-metabolizing enzymes.Correspondence to:
Prof. Dr. U. Fuhr; Institut für Pharmakologie, Klinische Pharmakologie, Universität zu Köln, Gleueler Straße 24, D-50931 Köln, Germany

Abstract

I.-W. Kim¹, K.-S. Choo¹, T.-G. Han¹, K.-S. Kim², S.-J. Chung¹, M.-H. Lee¹ and C.-K. Shim¹

¹Department of Pharmaceutics, College of Pharmacy, Seoul National University, and ²Soon Hwa Hospital, Seoul, Korea
The objective of this study was to determine the extent of period effect on the pharmacokineitcs of loxoprofen during consecutive dosing. Loxipen and Loxonin tablets were administered to 16 healthy Korean male subjects at a single dose of 60 mg as loxoprofen sodium anhydrous in a 2 × 2 crossover investigation with a two-week wash-out phase. Concentrations of loxoprofen in plasma were measured by HPLC method for 6 h. The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there was a significant (p < 0.05) period effect in AUCinf (area under the plasma concentration-time curve from time zero to infinity) between the administrations. A 20% decrease in the AUC was seen at the second administration. This period effect on pharmacokinetics of loxoprofen may be relevant for the patients who need consecutive administration of the drug.Correspondence to:
Dr. M.-H. Lee; Department of Pharmaceutics, College of Pharmacy, Seoul National University, San 56-1, Shinlim-dong, Kwanak-gu, Seoul 151-742, Korea

Abstract

F. Singer¹, F. Mayrhofer², G. Klein³, R. Hawel⁴ and C.J. Kollenz⁵

¹Sonderkrankenanstalt Laab im Walde, Laab im Walde, ²Sonderkrankenanstalt Bad Schallerbach, Rehabilitationszentrum für rheumatische, orthopädische und neurologische Erkrankungen, Bad Schallerbach, ³Sonderkrankenanstalt für rheumatische Erkrankungen und Herz-Kreislauf-Krankheiten und Ludwig-Boltzmann-Institut für Rehabilitation interner Erkrankungen, Saalfelden, ⁴Rehabilitationszentrum Bad Hofgastein, Bad Hofgastein and ⁵Medical Department Gebro Pharma GmbH, Fieberbrunn, Austria
Objective: Treatment with non-steroidal anti-inflammatory drugs is the most common pharmacological therapy of rheumatic diseases. For the symptomatic treatment of painful disorders a dose-response relationship of the NSAID should be a basic requirement, which is difficult to be proven in studies because rheumatic diseases are heterogenous in terms of clinical involvement. The aim of this double-blind randomized trial was to compare the isolated active enantiomer dexibuprofen (S(+)-ibuprofen) with the double dose of racemic ibuprofen and to show a dose-response relationship of dexibuprofen in painful osteoarthritis of the hip. Methods: 178 patients were randomly assigned to dexibuprofen 600/1200 mg or racemic ibuprofen 2400 mg daily. The primary endpoint was the improvement of the WOMAC osteoarthritis index after 15 days of therapy. The analysis was by intention to treat. Results: The evaluation of the WOMAC OA index showed statistically significant equivalence of dexibuprofen 400 mg t.i.d. compared with racemic ibuprofen 800 mg t.i.d. by a Mann-Whitney statistic of 0.578 and the corresponding lower bound of the 95% confidence interval of 0.498. The test for superiority of dexibuprofen was borderline significant with p = 0.055. Dexibuprofen 400 mg t.i.d. and dexibuprofen 200 mg t.i.d. showed a statistically significant dose-response relationship in improving the WOMAC OA index (p = 0.023). Patients suffered from adverse drug reactions, mainly gastrointestinal disorders, 13.34% on dexibuprofen 200 mg, 15.25% on dexibuprofen 400 mg and 16.94% on racemic ibuprofen 800 mg. Conclusions: The active enantiomer dexibuprofen (S(+)-ibuprofen) proved to be an effective non-steroidal anti-inflammatory drug with a significant dose-response relationship in patients with painful osteoarthritis of the hip. Compared with racemic ibuprofen half of the daily dose of dexibuprofen shows at least equivalent efficacy. In contrast to pharmacokinetic data, the additional administration of R(–)-ibuprofen in form of racemate does not contribute to the clinical efficacy of racemic ibuprofen.Correspondence to:
Dr. C.J. Kollenz; Medical Department, Gebro Pharma GmbH, A-6391 Fieberbrunn, Austria

Abstract

H. Kodama¹, Y. Kodama², S. Shinozawa¹, R. Kanemaru³, N. Itokazu⁴ and T. Sugimoto⁴

¹Departments of Pharmacy and ⁴Pediatrics, Miyazaki Medical College Hospital, Miyazaki, ²Department of Clinical Pharmacology, Jichi Medical School, Tochigi, and ³Kanemaru Neurosurgery Hospital, Miyazaki, Japan
Aim: The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the pediatric population. Binding parameters of PHT to serum proteins in our study were conducted to compare with in vivo or in vitro binding parameters of PHT to serum proteins in adult subjects reported by other investigators. Subjects and materials: Serum samples in the study were obtained from 40 pediatric patients (16 male, 24 female) receiving PHT monotherapy. Their age ranged from 1 to 15 years (9.2 ± 3.6 years, mean ± SD). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. Results: The association constant (Ka) was 0.014 l/mmol, while the total concentration of binding sites (n(Pt)) was 747 mmol/l. The number of binding sites per albumin molecule (n) was 1.13, while binding ability (n×Ka) was 0.016 l/mmol. The fu was 0.087. The n×Ka is approximately 1.2 times higher in PHT monotherapy adult patients of Pospísil et al. [1992] (i.e. 0.0191 l/mmol) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al. [1978] (i.e. 0.0186 l/mmol) than in our study, while n is similar between the two studies. The fu in our pediatric patients is similar to the unbound serum PHT fraction in adult patients receiving PHT therapy reported by Richens [1979] (i.e. 0.1). Conclusion: Our results suggest that there may be small differences in the binding characteristics of PHT to serum proteins between Japanese pediatric and non-Japanese adult subjects. The unbound serum fraction of PHT in pediatric patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of PHT.Correspondence to:
Dr. H. Kodama; Department of Pharmacy, Miyazaki Medical College Hospital, 5200, Kiyotake-machi, Miyazaki-gun, Miyazaki, 889-1692, Japan

Abstract

K. Farker¹, M.H. Lehmann¹, R. Kästner¹, J. Weber³, V. Janitzky², J. Schubert² and A. Hoffmann¹

¹Institute of Clinical Pharmacology, ²Clinic for Urology, Friedrich Schiller University Jena, ³Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany
Objective: Genetic polymorphisms of human cytochrome P450s have been implicated to be of importance for susceptibility to different cancers. Recently, a point mutation was found in the exon 2 of the CYP2E1 gene (CYP2E1*2) [Hu et al. 1997]. In order to evaluate a possible link between the point mutation in exon 2 of the CYP2E1 gene and the susceptibility to renal cell/ urothelial cancer, we developed a screening method based on the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Material: DNA of peripheral white blood cells was isolated from 158 renal cell/urothelial cancer patients as well as from 150 controls. Method: Primers for PCR were designed by the Primer 3 release 0.1 program. The PCR yield a product of 215 base pairs (bp), which was digested with the restriction enzyme Hha I. The DNA fragments were separated on a 3% agarose gel stained with ethidium bromide. Restriction enzyme digestion of the PCR product obtained from the wild-type DNA resulted in the appearance of a 66 bp, a 43 bp, a 40 bp, a 39 bp and a 28 bp DNA fragment. In contrast to the wild-type, the digestion of the PCR product from DNA carrying the point mutation resulted in the loss of the 39 bp and 40 bp fragments and the appearance of an additional 79 bp fragment. Therefore, the loss of one Hha I restriction site caused by a single nucleotide exchange is suitable for the identification of the point mutation in exon 2 of CYP2E1 gene. Results: However, we could not detect any point mutation in any of the 158 renal cell/urothelial cancer patients or the 150 controls. The distribution of the point mutation in exon 2 of CYP2E1 gene did not show any difference in renal cell/urothelial cancer patients and controls. Conclusion: This might indicate a lack of association between this CYP2E1 polymorphism (CYP2E1*2) and renal cell/urothelial cancer.Correspondence to:
Dr. K. Farker; Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Dornburger Straße 159, D-07740 Jena, Germany

Abstract

M.J. Garrido¹, C. Aguirre¹, I.F. Trocóniz¹, M. Marot², M. Valle¹, M.K. Zamacona¹ and R. Calvo¹

¹Department of Pharmacology, School of Medicine, University of the Basque Country, Leioa, and ²Department of Psychiatry, Galdakao Hospital, Galdakao, Vizcaya, Spain
Objective: To quantify serum protein levels and protein-binding of methadone in vitro in heroin-addicted patients showing objective signs of heroin abstinence. Subjects and methods: Serum samples were obtained from patients (n = 27) hospitalized to participate in a methadone detoxification program and from healthy volunteers (n = 21). The severity of the abstinence syndrome was assessed before blood sampling using a standardized scale. Concentrations of both albumin and a1-acid glycoprotein (AAG) were measured in all serum samples. The protein-binding of a1-methadone was determined by the ultrafiltration technique and the unbound concentration was measured by liquid scintillation counting. Results: The mean of the AAG concentrations was significantly increased in patients showing signs of withdrawal while the albumin concentrations did not change. Also, the unbound methadone was significantly decreased in this group when compared to the control. A positive correlation (Pearson r = 0.48; p < 0.005) indicates that AAG levels rise during abstinence as the score of withdrawal symptoms increases. Additionally, pooled data from all individuals show the binding of methadone to be related to AAG (r = 0.46; p < 0.05) levels and not to albumin. Conclusions: The observed changes in protein-binding in abstinence individuals suggest the need for increased dosages of methadone when such patients are treated. Levels of AAG or protein-binding appear to be components of the interindividual variance observed in the response to methadone treatment, hence these variables could be included in future kinetic and dynamic studies.Correspondence to:
Dr. R. Calvo Dúo; Departamento Farmacologia, Facultad de Medicina, Universidad del Pais Vasco, E-48940 Leioa, Vizcaya, Spain

Abstract

J. Martens-Lobenhoffer¹, J. Fuhlroth² and K. Ridwelski²

¹Institute of Clinical Pharmacology ²Division of General Surgery University Hospital, Magdeburg, Germany
A high dose antineoplastic therapy with 5-fluorouracil (5-FU) is associated with severe side effects. It is thought that the cytoprotective drug amifostine can reduce these side effects when it is given prior to a chemotherapeutic course. In this study, the pharmacokinetic parameters of 5-FU are monitored in six patients, who received two chemotherapeutic courses of 2600 mg/m2 BSA 5FU over 24 h, one course with 700 mg/m2 BSA amifostine prior to the 5-FU infusion and the other without. 20 serum samples were drawn during each infusion time and the 5-FU concentrations were determined by a sensitive and selective GC-MS assay. The statistical analysis of the serum concentrations revealed no significant differences in the pharmacokinetic parameters of 5-FU, whether amifostine is administered or not. The conclusion can be drawn that a reduction of side effects is due to the cytoprotective effect of amifostine and not to a change in the serum concentrations of 5-FU.Correspondence to:
Dr. J. Martens-Lobenhoffer; Institut für klinische Pharmakologie, Otto-von-Guericke Universität, Leipziger Strasse 44, D-39120 Magdeburg, Germany

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Volume 38, No. 1/2000(January)