Pharmacokinetics
Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation
F. Sörgel, U. Fuhr, M. Minic, M. Siegmund, J. Maares, A. Jetter, M. Kinzig- Schippers, D. Tomalik-Scharte, J. Szymanski, T. Goeser, U. Toex, B. Scheidel and W. Lehmacher
Price
42.00 $
Volume 43 p. 140 - 149
Abstract
F. Sörgel1, U. Fuhr2, M. Minic3, M. Siegmund4, J. Maares4, A. Jetter2, M. Kinzig- Schippers2, D. Tomalik-Scharte2, J. Szymanski2, T. Goeser5, U. Toex5, B. Scheidel1 and W. Lehmacher6
1Institute for Biomedical and Pharmaceutical Research, Nuremberg-Heroldsberg, 2University of Cologne, Department of Pharmacology, Clinical Pharmacology, Cologne, Germany, 3F. Hoffmann-La Roche Ltd., Basel, 4Roche Consumer Health Ltd., Kaiseraugst, Switzerland, 5University of Cologne, Department of Gastroenterology and 6University of Cologne, Department of Medical Statistics, Cologne, Germany
Objective: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. Material and Method: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 × 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 × 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. Results: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar Cmax to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the tmax for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. Conclusions: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.Correspondence to:
Prof. Dr. F. Sörgel; Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Straße 19,
90562 Nürnberg-Heroldsberg, Germany
Email: [email protected]
Drug Metabolism
Rate-limiting biotransformation of triamterene is mediated by CYP1A2
U. Fuhr, S. Kober, M. Zaigler, E. Mutschler and H. Spahn-Langguth
Price
42.00 $
Volume 43 p. 327 - 334
Abstract
U. Fuhr, S. Kober, M. Zaigler, E. Mutschler and H. Spahn-Langguth
1Institute for Pharmacology, Clinical Pharmacology, University of Cologne, 2Department of Pharmacology, Biocenter Niederursel N260, Frankfurt/Main, and 3Department of Pharmaceutical Chemistry, Martin Luther University Halle-Wittenberg, Halle/Saale, German
Objective: Triamterene (TA), a potassium-sparing diuretic, is extensively metabolized by hydroxylation in 4?-position and subsequent conjugation by cytosolic sulfotransferases. To identify the cytochrome P450 enzyme(s) catalyzing hydroxylation of triamterene (the rate-limiting step in the formation of the sulfate ester (STA)), in vitro incubation studies were performed with human liver microsomes. Methods: Initial rates of TA hydroxylation (0 ? 300 Correspondence to:
Prof. Dr. H. Spahn-Langguth
Spessartstra
Email: [email protected]
Extended Abstracts
Individual variation in factors affecting the steps between dose application and effects of antineoplastic agents
U. Fuhr and J. Kirchheiner
Price
42.00 $
Volume 43 p. 573 - 574
Abstract
U. Fuhr and J. Kirchheiner
Pharmacogenetics
CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH)
A. Lazar, H. Menzel, I. Cascorbi, G. Kümel, M. Sachs, S. Rietbrock, I. Roots and U. Fuhr
Price
42.00 $
Volume 42 p. 78 - 82
Abstract
A. Lazar1, H. Menzel1,2, I. Cascorbi5, G. Kümel1, M. Sachs3, S. Rietbrock1,2, I. Roots4 and U. Fuhr1,2
1Department of Pharmacology, University Hospital, University of Cologne, Clinical Pharmacology, 2Pharmazentrum Frankfurt, Klinikum der Johann-Wolfgang-Goethe-Universität, 3Clinic of General Surgery, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, 4Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, and 5Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany
Objective: Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. Method: Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. Results: Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% CI 0.23 – 2.44), 0.72 (95% CI 0.10 – 5.34) and 1.96 (95% CI 0.59 – 6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. Conclusion: The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.
Pharmacokinetics
Absorption pattern of trospium chloride along the human gastrointestinal tract assessed using local enteral administration
S. Schröder, A. Jetter, M. Zaigler, R. Weyhenmeyer, G. Krumbiegel, W. Wächter and U. Fuhr
Price
42.00 $
Volume 42 p. 543 - 549
Abstract
S. Schröder1, A. Jetter1, M. Zaigler1, R. Weyhenmeyer2, G. Krumbiegel2, W. Wächter2 and U. Fuhr1
1Department of Pharmacology, Clinical Pharmacology, University of Cologne, Cologne, and 2Madaus AG, Cologne, Germany
Background and objectives: The antimuscarinic drug trospium chloride is hydrophilic and therefore does not enter the CNS when used for the treatment of overactive bladder disturbances. However, the same property is the main reason for low and variable oral bioavailability. The present study was performed to assess the influence of intestinal site on absorption of the drug as the basis for the development of modified release preparations. Methods: In a change-over pilot study, 8 healthy male volunteers received single 20 mg doses of trospium chloride orally as a tablet (reference), as Eudragit-coated tablets dissolving at pH 6.0 (local administration into the small intestine), and rectally via a mini enema (corresponding to local administration into the large intestine). Plasma concentrations of trospium chloride were determined up to 36 hours after administration using GC/MS. Results: Extent and rate of trospium chloride absorption declined rapidly upon administration into more distal regions of the gastrointestinal tract. Cmax (median: 6.42 ng/ml) and AUC(0-tlast) (42.28 ng/ml × h) were highest and tmax (3.5 h) was shortest after administration of the reference tablet. AUC(0-tlast) reached 78% (90% CI 43 – 139%) after small intestine administration and 2% (90% CI 1 – 9%) following rectal administration, respectively, relative to the values for the oral tablet. Conclusion: Trospium chloride is absorbed primarily in the upper gastrointestinal tract. Development of modified release preparations must balance prolonged apparent absorption rates of the drug against a decrease in bioavailability.
Correspondence to:
Prof. Dr. U. Fuhr
Department of Pharmacology
University of Cologne, Clinical Pharmacology
Gleueler Straße 24
D-50931 Köln, Germany
Email: [email protected]
Therapeutics
The role of active metabolites in dihydrocodeine effects
H. Schmidt, S.V. Vormfelde, M. Walchner-Bonjean, K. Klinder, S. Freudenthaler, C.H. Gleiter, U. Gundert-Remy, G. Skopp, R. Aderjan and U. Fuhr
Price
42.00 $
Volume 41 p. 95 - 106
Abstract
H. Schmidt, S.V. Vormfelde, M. Walchner-Bonjean, K. Klinder, S. Freudenthaler, C.H. Gleiter, U. Gundert-Remy, G. Skopp, R. Aderjan and U. Fuhr
1pharmazentrum frankfurt, Clinical Pharmacology, University of Frankfurt, 2Institute of Clinical Pharmacology, University of Göttingen, 3Institute of Pharmacology, Clinical Pharmacology, University of Köln, 4Institute of Forensic Medicine, University of Heidelberg, 5Department of Clinical Pharmacology, University of Tübingen, and 6BgVV, Berlin, Germany
Objective: The metabolism of dihydrocodeine to dihydromorphine, a high affinity m-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. Methods: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. Results: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. Conclusion: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
Extended Abstract
Population pharmacokinetics of etoposide*
S. Reif, A. Jetter, U. Fuhr, H. McLeod, D. Kingreen, W. Siegert and U. Jaehde
Price
42.00 $
Volume 40 p. 578 - 579
Abstract
S. Reif1, A. Jetter2, U. Fuhr2, H. McLeod3, D. Kingreen4, W. Siegert4 and U. Jaehde1,5
Extended Abstract
Population pharmacokinetics of cyclo- phosphamide, doxorubicin and etoposide in 30 patients with BEACOPP chemotherapy
S. Wilde, A. Jetter, M. Zaigler, S. Rietbrock, H. Menzel, M. Sieber, H. Tesch, G. Hempel, D. Busse, M. Schwab, S. Reif, U. Jaehde, V. Diehl and U. Fuhr
Price
42.00 $
Volume 40 p. 586 - 588
Abstract
S. Wilde1, A. Jetter1, M. Zaigler1, S. Rietbrock1, H. Menzel1, M. Sieber2, H. Tesch2, G. Hempel3, D. Busse4, M. Schwab4, S. Reif5, U. Jaehde5, V. Diehl2 and U. Fuhr1
Cytostatics and CYP3A4
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes
M. Baumhäkel, D. Kasel, R.A. Rao-Schymanski, R. Böcker, K.T. Beckurts, M. Zaigler, D. Barthold and U. Fuhr
Price
42.00 $
Volume 39 p. 517 - 528
Abstract
M. Baumhäkel1, D. Kasel1, R.A. Rao-Schymanski1, R. Böcker2, K.T. Beckurts3, M. Zaigler1, D. Barthold1 and U. Fuhr1
1Clinical Pharmacology, Institute for Pharmacology, University of Köln, 2Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, and 3Department of Visceral and Vascular Surgery, University of Köln, Germany
Background: The human cytochrome P450 enzyme CYP3A4 is involved in the metabolism of many anticancer drugs. Since these drugs are usually administered in a polychemotherapy regimen, the objective of this study was to examine their inhibitory potency on CYP3A4 with regard to possible mutual drug interactions. Method: CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 mM (= KM). Formation of the pyridine metabolite was measured using HPLC. Inhibitor concentrations used were 0.5, 5 and 50 mg/ml, except for cyclophosphamide and ifosfamide (0.5, 2.5 and 5 mg/ml) and for paclitaxel (0.05, 0.15, 0.5, 1.5 and 5 mg/ml). Results: The following substances showed an inhibitory effect on CYP3A4 (IC50 values for the 2 microsome samples are parenthesized): cyclophosphamide (12.3/9.2 mmol/l), mafosfamide generated 4-OH-cyclophosphamide (152/163 mmol/l), ifosfamide (3.6/2.5 mmol/l), vinblastine sulfate (20/44 mmol/l), vincristine sulfate (67/176 mmol/l), daunorubicin hydrochloride (206/200 mmol/l), doxorubicin hydrochloride (160/215 mmol/l), teniposide (64/84 mmol/l) and docetaxel (6.4/12.7 mmol/l). No inhibitory effect on CYP3A4 was observed with epirubicin, etoposide, paclitaxel, cytarabine, 5-FU, 6-mercaptopurine, methotrexate, cisplatin, carboplatin, bleomycin, busulfan, chlorambucil and mitomycin. Conclusion: Comparing IC50 values with plasma concentrations present during antineoplastic therapy, the agents cyclophosphamide, ifosfamide, vinblastine, teniposide and docetaxel could possibly cause clinical drug interactions by inhibition of CYP3A4. Some recently described clinical interactions with antineoplastic agents may be explained by these results.Correspondence to:
Prof. Dr. U. Fuhr; Institut für Pharmakologie, Klinische Pharmakologie, Universität zu Köln,
Gleueler Straße 24, D-50931 Köln, Germany
Email: [email protected]
Original
Problems and perspectives of phenotyping for drug-metabolizing enzymes in man
M. Zaigler, I. Tantcheva-Poór and U. Fuhr
Price
42.00 $
Volume 38 p. 1 - 9
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
Original
Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women
M. Zaigler, S. Rietbrock, J. Szymanski, J.S.E. Dericks-Tan, A.H. Staib and U. Fuhr
Price
42.00 $
Volume 38 p. 235 - 244
Abstract
M. Zaigler1,2, S. Rietbrock1,2, J. Szymanski2, J.S.E. Dericks-Tan3, A.H. Staib2 and U. Fuhr1,2
1Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, 2Institute for Clinical Pharmacology, and 3Department of Gynaecological Endocrinology, Centre for Gynaecology and Obstetrics, University Hospital, Frankfurt am Main, Germany
Background and objectives: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP1A2 activity is not clear. Methods: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean ± SD) 27.8 ± 3.8 years, body mass index 23.8 ± 3.8 kg × m–2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 ± 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. Results: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day –9 to –4 prior to onset of the next menses) to the follicular phase (days 5 – 10) was (n = 13, point estimate) 1.03 (90% CI 0.95 – 1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. Conclusions: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.Correspondence to:
Prof. Dr. med. U. Fuhr; Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, Gleueler Straße 24, D-50931 Köln, Germany
