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  • 7-hydroxy-methotrexate  (2)
  • individual bioequivalence  (2)
  • Computer-based learning environments  (1)
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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 499-513 
    Details
    ISSN: 1573-8744
    Keywords: methotrexate ; 7-hydroxy-methotrexate ; pharmacokinetics ; nonlinear pharmacokinetics ; dose-dependent pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2–27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (Vss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger Vss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062208
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Clearance studies of methotrexate and 7-hydroxy-methotrexate in rabbits after multiple-dose infusion (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 515-527 
    Details
    ISSN: 1573-8744
    Keywords: total body clearance ; renal clearance ; methotrexate ; 7-hydroxy-methotrexate ; nonlinearity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The concentration-dependent clearance of methotrexate (MTX) and its metabolite, 7-hydroxy-methotrexate (7-OH-MTX), was demonstrated in 5 rabbits using 7 infusion rates (10.5–323 mg/hr). Mean total body clearance (from 34.3 to 13.1 ml/min) and mean renal clearance (from 25.6 to 7.6 ml/min) of MTX were found to decrease with increasing steady-state plasma concentrations (from 5.1 to 412 μg/ml), whereas nonrenal clearances remained relatively constant. An essentially steady-state plasma level of 7-OH-MTX was achieved during each MTX infusion, and its renal clearance also decreased (from 37.3 to 6.5 ml/min) with increasing metabolite levels (from 1.8 to 293 μg/ml). Saturable renal tubular secretion appeared operative for both drug and metabolite since their renal clearance (based on the free drug) to inulin clearance ratios were much greater than unity and the ratios were markedly reduced in 2 rabbits after probenecid treatment. Plasma protein binding of MTX (56%) and 7-OH-MTX (49%) were independent of concentrations between 0.1 and 300 μg/ml. Negligible MTX metabolism was found in rabbit kidney homogenates, thus validating renal clearance measurement in the present study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062209
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Subject-by-Formulation Interaction in Bioequivalence: Conceptual and Statistical Issues (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 375-380 
    Details
    ISSN: 1573-904X
    Keywords: individual bioequivalence ; within-subject variability ; subject-by-formulation interaction ; subgroups
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The FDA has proposed replacing the current averagebioequivalence criterion with population and individual bioequivalence criteriathat consider variances in addition to the difference of averages. Oneof these variances in the individual bioequivalence criterion measuressubject-by-formulation interaction, the extent to which thetest-reference difference varies from person to person. This paper discussesconceptual and statistical issues raised in various publications andpresentations with respect to the presence and estimation of such aninteraction. Methods. We focus on the importance of subject-by-formulationinteraction, an understanding of what is a large interaction, and theassessment of the magnitude of this interaction in bioequivalence studies.Simulation studies, examples from the literature, and data from FDAfiles are used to demonstrate the magnitude of the interaction and itsdistribution under various conditions. Results. The concept of a large interaction is tied to the concept of alarge mean difference. We suggest that an interaction greater than0.15 is a conservative criterion for a large interaction. Magnitudes ofestimated interaction are affected by variability, sample size, and theselection of data sets that pass average bioequivalence. Conclusions. Examples of substantial interactions are beginning toappear. More data is needed before reaching definitive conclusionsregarding the frequency and importance of observed interactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007508516231
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Bioequivalence of Methylphenidate Immediate-Release Tablets Using a Replicated Study Design to Characterize Intrasubject Variability (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 381-384 
    Details
    ISSN: 1573-904X
    Keywords: methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007560500301
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    A methodology for characterizing computer-based learning environments (1995)
    Springer
    Instructional science 23 (1995), S. 183-220 
    Details
    ISSN: 1573-1952
    Keywords: Computer-based learning environments ; characterization ; theory-based evaluation ; theories of learning and instruction ; cognitive theories of knowledge acquisition ; interaction ; research methodology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Education
    Notes: Abstract This paper presents a methodology for characterizing computer-based learning environments, focusing on the cognitive, pedagogical, and interactive features. The framework for this characterization is explained in relation to the relevant theories and findings in cognitive and instructional research. The methodology is illustrated by a characterization of computer-based learning environments developed by student teachers and professionals. The usability of these environments is analyzed along the dimensions of the framework presented. The results showed that this methodology can systematically and precisely characterize the cognitive, pedagogical, and interactive features of computer-based learning environments. It can be used to predict and explain the success or failure that a given software program promotes for learning particular types of knowledge. The applications of this methodology for the evaluation and design of computer-based learning environments, for instructional research in various instructional contexts, as well as for the study of expertise in the development of computer-based learning environments, are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00890451
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    Paper (German National Licenses)
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