Library

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Electronic Resource
    Electronic Resource
    The Role of Metabolites in Bioequivalency Assessment. II. Drugs with Linear Pharmacokinetics and First-Pass Effect (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 700-708 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; rate of absorption ; rate of availability ; parent drug ; metabolite ; linear pharmacokinetics ; first-pass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Simulations were conducted to address the question of whether metabolite data are required for bioequivalence evaluation of immediate release formulations with drugs exhibiting linear pharmacokinetics and first-pass effect. Plasma level-time profiles were generated for parent drug and metabolite using relevant rate constants obtained from a bivariate normal distribution and designated random error. Simulation results showed that the need for metabolite data (Cmax) in the assessment of bioequivalence depends on the relative variability between the absorption process of the drug and first-pass route for metabolite(s). The importance of metabolite Cmax data in the evaluation of rate of availability is clearly demonstrated for drugs with a high degree of intra-subject variation in the first-pass metabolism compared to the absorption process of the drug. Under such conditions, a wider confidence interval was found for the metabolite rather than parent drug. Opposite results were obtained when the intra-subject variance was high for drug absorption relative to first-pass effect. Discrepancies were observed for the scenarios in which the elimination pathway of the metabolite is more variable than the absorption process of the drug. The simulation results were in agreement with real bioequivalence data. It is thus recommended that, in the absence of the information on the relative variability of absorption and first-pass process, both parent drug and metabolite data be included for documentation of bioequivalence, should the metabolite(s) play an important role in the determination of efficacy and safety of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016259509257
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    The Role of Metabolites in Bioequivalency Assessment. I. Linear Pharmacokinetics without First-Pass Effect (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 25-32 
    Details
    ISSN: 1573-904X
    Keywords: parent drug ; metabolite ; bioequivalence ; absorption rate ; peak concentration ; time to peak
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using C maxof parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of C max values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for C max of the metabolite and, in turn, a tighter confidence interval for C max of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for C max of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015865920043
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 4
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...