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  • 1
    Electronic Resource
    Electronic Resource
    An Equation for the Systemic Availability of Drugs Undergoing Simultaneous Enterohepatic Cycling, First-Pass Metabolism, and Intestinal Elimination (1987)
    Springer
    Pharmaceutical research 4 (1987), S. 195-199 
    Details
    ISSN: 1573-904X
    Keywords: enterohepatic recirculation ; pharmacokinetics ; bioavailability ; area under the curve ; bile ; hepatic extraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A relationship between systemic availability and its determinants has been derived for a physiologically realistic model of drug disposition that includes enterohepatic cycling (EHC), gallbladder emptying (with an arbitrary time course), first-pass metabolism to noncycling metabolites, and fecal excretion. Systemic availability (F) has been shown to be determined by the fraction of the dose initially absorbed (f a*), the fraction of the drug excreted into the GI tract that is reabsorbed with each cycle (f a), the hepatic extraction ratio (E), and the fraction of extracted drug that is transported to the gallbladder for EHC (f g) according to the relationship F = f a*(1 −E/(1 − f a f g E) The implications of the above relationship are that (1) systemic availability is dependent on EHC, (2) values of F calculated to be greater than unity cannot be explained simply by the presence of EHC, (3) calculations of E based on the usual expression F = f a* (1 − E) are erroneous for drugs subject to EHC, and (4) a compound that has a high systemic availability and is subject to EHC is not necessarily inefficiently metabolized. The quantitative interrelationship of systemic availability and its determinants is illustrated using a contour plot. Slices through the surface are used to demonstrate that the presence of EHC changes the sensitivity of F to changes in E.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016447826075
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  • 2
    Electronic Resource
    Electronic Resource
    Influence of Dose Range on Degree of Nonlinearity Detected in Dose-Proportionality Studies for Drugs with Saturable Elimination: Single-Dose and Steady-State Studies (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 289-293 
    Details
    ISSN: 1573-904X
    Keywords: dose proportionality ; Michaelis–Menten ; nonlinearity ; data analysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Deviation from proportionality occurs when the ratio of area under the curve (AUC) values is not equal to the ratio of administered doses. The degree of nonlinearity (f NL) can be quantitated as the ratio of AUCs divided by the ratio of doses. We explore positive deviation from proportionality (f NL 〉 1) using the classical Michaelis–Menten model of nonlinear elimination after a single dose (n = 1) or at steady state (ss). The degree of nonlinearity is related to the ratio of the highest dose to the lowest dose (Rd = D H/D L): f NL n=1 = (2 + Rd · ε)/(2 + ε), f NL ss= (Rd · Ω −1) /(Rd · Ω −Rd), where ε is the ratio of the initial concentration after the lowest dose to the K m (ε = D L/K m · V) and Ω is the ratio of the V max to the average rate of input for the highest dose (Ω = V maxτ/F · D H). From these relationships, we find that (1) for single-dose studies, K m is the important Michaelis–Menten parameter, while V max is important at steady state; (2) the degree of nonlinearity cannot exceed the ratio of doses in single-dose studies, and when doses in extreme excess of K m· V are chosen, the degree of nonlinearity is equal to the dose range; and (3) at steady state, the degree of nonlinearity can exceed the ratio of doses and approaches infinity as the average input rate approaches V max. Literature data (phenytoin and ethanol) support these findings. We conclude that the degree of nonlinearity is not a useful measure of nonlinearity in and of itself and propose percentage saturation as being more informative.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018955315055
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  • 3
    Electronic Resource
    Electronic Resource
    Mean residence time for drugs subject to enterohepatic cycling (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 327-345 
    Details
    ISSN: 1573-8744
    Keywords: enterohepatic recirculation ; pharmacokinetics ; hepatic extraction ; area under the first moment curve ; model ; bile ; mean residence time ; mean absorption time ; formulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologically realistic model of enterohepatic cycling (EHC) which includes separate liver and gallbladder compartments, discontinuous gallbladder emptying and first-order absorption from both an oral formulation and secreted bile (ka po and ka b, respectively) has been developed. The effect of EHC on area under the first-moment curve (AUMC) of drug concentration in plasma and on parameters derived from the AUMC was investigated. Unlike AUC, AUMC is dependent on the time and time-course of gallbladder emptying, increasing as the interval between gallbladder emptying increases. Consequently, mean residence time (MRT) is also a time-dependent parameter. Analytical solutions for MRTiv and MRTpo were derived. Mean absorption time (MAT = MRTpo — MRTivj is also time-dependent, contrary to findings previously published for a model of EHC with a continuous time lag. MAT is also dependent on k a po , k a b and the hepatic extraction ratio. The difference between MRT po s two formulations with unequal k a po values may deviate from the difference in the inverse of their absorption rate constants. Implications for design and interpretation of pharmacokinetic studies include (i) MAT values may be dominated by the time-course of recycling rather than the time-course of the initial absorption, depending on the extent of EHC and (ii) the unpredictable nature of the time of gallbladder emptying will contribute to intrasubject variability in derived parameters during crossover studies. Knowledge of the extent of EHC is invaluable in deciding whether modification of the in vitro release characteristics of an oral formulation will have any effect on the overall time-course of absorption in vivo. Techniques to monitor or control gallbladder emptying may be helpful for reducing variability in pharmaco-kinetic studies for compounds which are extensively cycled in bile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061900
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  • 4
    Electronic Resource
    Electronic Resource
    Estimation of area under the curve for drugs subject to enterohepatic cycling (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 589-608 
    Details
    ISSN: 1573-8744
    Keywords: enterohepatic recirculation ; pharmacokinetics ; hepatic extraction ; area under the curve ; model ; bile ; simulated concentration-time curves
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologically realistic model is used to provide insight into the design of sampling protocols for accurate determination of AUC(0– ∞) for drugs subject to enterohepatic cycling. Through simulation of plasma concentration- time curves for such drugs it is found that (1) more than one peak is predicted after oral and intravenous administration of a single dose of drug, (2) the relative magnitude of peaks is dependent on the hepatic extraction ratio for both oral and intravenous drug administration, (3) the percent of the AUC(0– ∞) in later time intervals is also a function of the hepatic extraction ratio, and (4) present methods for the design of sampling protocols may not provide accurate estimates of AUC(0– ∞) (especially for highly extracted drugs), because (a) peaks are only evident at later times after intravenous administration when plasma sampling is less frequent, (b) much of the area occurs at later times, and (c) the amount of drug in the sampling compartment after oral administration is much lower than that after intravenous administration of drug and could be incorrectly interpreted as low bioavailability if sampling is not carried out for a long period of time. The types of oral and intravenous profiles predicted for highly extracted drugs are exemplified by data for naltrexone in the monkey.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01058903
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    Paper (German National Licenses)
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