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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic characterization of the antiarrhythmic drug diprafenone in man (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 313-316 
    Details
    ISSN: 1432-1041
    Keywords: diprafenone ; pharmacokinetics ; bioavailability ; first-pass metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the antiarrhythmic drug diprafenone have been investigated in 6 healthy volunteers following single intravenous (50 mg) and oral doses (50 and 150 mg). Diprafenone was mainly eliminated by metabolism in the liver. Following i.v. infusion of 50 mg diprafenone, the terminal half-life of elimination was 1.50 h, the volume of distribution at steady-state was 1.23 l·kg−1, and the free fraction in plasma was 1.68%. Mean total plasma clearance was 741 ml·min−1·70 kg−1, which approaches normal liver blood flow after correction for the blood/plasma concentration ratio. Thus, diprafenone can be classified as a high extraction drug. Following oral administration, a dose-dependent increase in bioavailability from 10.9 (50 mg dose) to 32.5% (150 mg dose) was observed. The data suggest that diprafenone is subject to saturable hepatic first-pass metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00679792
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  • 2
    Electronic Resource
    Electronic Resource
    Clinical applicability of current pharmacokinetic models: Splanchnic elimination of 5-fluorouracil in cancer patients (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 229-249 
    Details
    ISSN: 1573-8744
    Keywords: Michaelis-Menten kinetics ; sinusoidal perfusion model ; venous equilibration model ; distributed model ; convection-dispersion model ; organ heterogeneity ; bioavailability ; pooling of data ; kinetic parameter estimation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of Vmax/Q= 48.0±11.6 (SD) μM for the pooled data set, where Vmax is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave K m=9.4μM,while the undistributed sinusoidal perfusion model gave K m * =26,5μM. With these values of K m,both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were Vmax/Q=41.0±5.1 (sem) μM,K m=8.4±1.3μM and K m * =23.2±3.2 μM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant K m + (K m + ⩽K m * ).A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields K m + values for individual patients which have a mean of 20.3±2.8 μM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062135
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  • 3
    Electronic Resource
    Electronic Resource
    A nonlinear physiologic pharmacokinetic model: I. Steady-state (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 73-92 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetic theory ; venous equilibration (“well-stirred”) model ; compartment model ; linear pharmacokinetics ; nonlinear pharmacokinetics ; bioavailability ; intrinsic clearance ; liver blood flow ; clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The two-compartment model of Rowland et al.,(2) has been extended by replacing first order elimination with Michaelis-Menten elimination kinetics. All of the equations for steady-state concentrations and clearances for zero order (constant rate) input orally (into compartment #2) and intravenously (into compartment #1) are derived and reported. The steady-state concentration in compartment #1, following intravenous administration, is shown to be a nonlinear function of maximal velocity of metabolism, Vm,the Michaelis constant, Km,and liver blood flow, Q;and, following oral administration is dependent only upon Vm and Km and is independent of Q.However, oral bioavailability is a function of Vm, Km,and Q.The model allows physiologic pharmacokinetic interpretation of both linear and nonlinear data; and, together with simple modification of the model, can explain much observed pharmacokinetic data to date particularly for first-pass drugs. Future articles in the series will be concerned with single doses, evaluation of literature data in terms of the model, application of the theory in toxicology and in clinical pharmacokinetics and therapeutics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01073657
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    Paper (German National Licenses)
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