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  • 1
    Electronic Resource
    Electronic Resource
    Novel Pharmacokinetic Modelling of Transdermal Nitroglycerin (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 614-619 
    Details
    ISSN: 1573-904X
    Keywords: population pharmacokinetics ; nitroglycerin ; 1,2-dinitroglycerin ; 1,3-dinitroglycerin ; transdermal administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To construct a pharmacokinetic (PK) model and to determine population PK parameters of nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN). Methods. Data were obtained in thirty healthy volunteers following a single dose of a GTN reservoir transdermal patch. Blood samples were obtained just before and at 0.5, 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours after the patch application and 1 hour after its removal. GTN, 1,2-GDN, and 1,3-GDN concentrations were determined using HPLC and simultaneously best fitted using a first-pass mixed-order release one-compartment PK model. Individual estimates (ADAPT-II) were used as priors for a population PK analysis (IT2S). Fitted parameters included the percentage (A) of the nitroglycerin dose reaching the systemic circulation that was released from the patch by a first-order process (K1); two absorption (ka1 and ka2), two metabolite formation (kfl and kf2) and one metabolite elimination (k(m)) rate constants; and three volumes of distribution Vc/F, V2/F and V3/F. Results. Nitroglycerin mean population parameter estimates and inter-individual variability (CV%) were: A 35% (65), K1, 0.06 h−1(91), ka1 5 h−1(46), ka2 0.47 h−1 (39), kf1 11 h−1(42), kf2 0.6 h−1(34), k(m) 1.4 h−1(29), Vc/F 6 L(31), V2 /F 73 L(34), and V3 /F 23 L(29). The average elimination half-lives for GTN and the two metabolites were 5 and 32 minutes, respectively. Conclusions. The proposed PK model fitted observed concentrations of GTN, 1,2-GDN and 1,3-GDN very well. This model should be useful to predict drug and metabolite concentrations and to assess bioequivalence of two transdermal formulations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011942213508
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  • 2
    Electronic Resource
    Electronic Resource
    A Population Analysis of Nebulized (R)-albuterol in Dogs Using a Novel Mixed Gut-Lung Absorption PK-PD Model (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1228-1235 
    Details
    ISSN: 1573-904X
    Keywords: (R)-albuterol ; enantiomer ; population pharmacokinetic analysis ; pharmacodynamics ; nebulization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objectives of this study were to 1) construct a pharmacokinetic-pharmacodynamic (PK-PD) model, and 2) determine the PKs and PDs of (R)-albuterol when given by nebulization to 8 dogs for 7 consecutive days. Methods. Four doses were evaluated (0.002, 0.02, 0.1, and 0.4 mg/kg/day). Blood samples were obtained after drug administration on days 1 and 7. Heart rates (HR) were obtained during treatment days 1, 4 and 7. All (R)-albuterol plasma concentrations were fitted using a mixed gut-lung absorption 2-compartment PK model. Day-1, 4, and 7 HR data were co-modeled using a direct response model with Hill-type equations, including a necessary tolerance phenomenon. The population PK-PD analysis was performed with an iterative 2-stage methodology (IT2S). Results. No chiral inversion was seen, and double absorption peaks on the plasma concentration versus time curves were observed in the majority of dogs. These were hypothesized to be the result of combined gut and lung absorption of (R)-Albuterol. Results indicated that 67% (range: 57-89%) of (R)-albuterol systemic exposure after nebulized administration is due to gut absorption. Mean population PK parameters were KaGI (10±5.7 h−1), KaLUNG (21±9.5 h−1), CLc/F (0.6±0.2 L/h/kg), CLd/F (1.4±0.5 L/h/kg), Vc/F (1.4±0.9 L/kg), and Vp/F (4.8±2.4 L/kg). (R)-albuterol administration was associated with an increase in the dogs heart rates. A tolerance effect related to the cumulative dose was observed and modeled. Conclusions. The presented PK-PD model appears to differentiate gut from lung absorption when (R)-albuterol is given by 15-minute nebulization to dogs. These results agree with the accepted hypothesis that most of the systemic exposure of (R)-albuterol after nebulized administration is due to gut absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026466730347
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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