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  • 1
    Electronic Resource
    Electronic Resource
    The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 365-379 
    Details
    ISSN: 1573-8744
    Keywords: disopyramide ; bioavailability ; protein binding ; nonlinear ; sustained release ; pharmacokinetics ; ultrafiltration ; immunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC,the area under the plasma concentration-time curve, is (1) nonlinear and (2) absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUCor area under the plasma unbound concentration-time curve (AUCu).The AUCand AUCugave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUCunder various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUCan insensitive parameter for the discrimination of products with different extents of bioavailability; immediate release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC tooverestimate the bioavailability of slower release products in single-dose studies; if AUCwere the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUCto product differences can be reinforced by the dependence of AUCon release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUCappears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCua feasible and more reliable index of bioavailability than AUCwhen plasma protein binding of drugs is nonlinear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059197
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 143-157 
    Details
    ISSN: 1573-8744
    Keywords: nitroglycerin ; dinitrate nitroglycerin metabolites ; end-product inhibition ; saturable binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 μg/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2-and 1,3-dinitraie metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10μg/min were 0.44±0.31, 1.32±0.71, 4.23±1.50 and 1.04±0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10μg/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 71 l/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11±6 l/min〈 as nitroglycerin concentrations initially increased.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059395
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of Formulation and Food on the Absorption of Hydrochlorothiazide and Triamterene or Amiloride from Combination Diuretic Products (1987)
    Springer
    Pharmaceutical research 4 (1987), S. 348-352 
    Details
    ISSN: 1573-904X
    Keywords: hydrochlorothiazide ; triamterene ; Dyazide ; Maxzide ; amiloride ; Moduretic ; food–drug interactions ; food-formulation interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016409606936
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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