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  • 1
    Electronic Resource
    Electronic Resource
    Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers (1997)
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. 531-533 
    Details
    ISSN: 1432-0843
    Keywords: Key words CYP2B6 ; Ifosfamide ; Phenytoin ; Metabolic induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Case: A suspected alteration in ifosfamide (IFF) metabolism and pharmacokinetics was observed in a pediatric patient receiving phenytoin. Methods: Sequential plasma samples were obtained and analyzed for the concentrations of the enantiomers of IFF and their N-dechloroethylated metabolites (DCE-IFF) using a validated enantioselective gas chromatographic-mass spectrometric method. Results: In the phenytoin-treated patient, the metabolic formation of IFF enantiomers was increased and the metabolic pattern of the N-dechloroethylation altered from non-phenytoin-treated patients: (R)-3-DCE IFF*(S)-3-DCE-IFF = (S)-2-DCE-IFF〉(R)-2-DCE-IFF (control) vs (S)-3-DCE-IFF = (S)-2-DCE-IFF〉(R)-3-DCE-IFF*(R)-2-DCE-IFF (patient). Conclusions: Previous studies have attributed the production of the (S)-2-DCE-IFF and (S)-3-DCE-IFF metabolites to the activity of CYP2B6 and (R)-2-DCE-IFF and (R)-3-DCE-IFF to the activity of CYP3A4. The results suggest that phenytoin induced the activity of CYP2B6 to a greater extent than CYP3A4. In addition, the patient, who was at least partially refractory to several other treatments, went into remission after IFF treatment suggesting that phenytoin pretreatment might increase IFF therapeutic efficacy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050698
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  • 2
    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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  • 3
    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
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  • 4
    Electronic Resource
    Electronic Resource
    New Insights into the Pharmacokinetics and Metabolism of (R,S)-Ifosfamide in Cancer Patients Using a Population Pharmacokinetic-Metabolism Model (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 645-652 
    Details
    ISSN: 1573-904X
    Keywords: (R,S)-Ifosfamide ; R2-, R3-, S2-, S3-DCE-IFF ; iterative-two stage analysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe the pharmacokinetics of R- andS-Ifosfamide (IFF), and their respective 2 and 3 N-dechloroethylated (DCE)metabolites (R2-, R3-, S2, S3-DCE-IFF) in cancer patients. Methods. (R,S)-IFF was administered (1.5 g/m2)daily for 5 days in 13 cancer patients. Plasma and urine samples were collectedand analyzed using an enantioselective GC-MS method. An average of 97observations per patient were simultaneously fitted using apharmacokinetic-metabolism (PK-MB) model. A population PK analysis was performedusing an iterative 2-stage method (IT2S). Results. Auto-induction of IFF metabolism was observed over the 5day period. Increases were seen in IFF clearance (R: 4 vs 7 L/h; S: 5vs 10 L/h), and in the formation of DCE (R: 7 vs 9%; S: 14 vs 19%)and active metabolites (4-OHM-IFF; R: 71 vs 77%; S: 67 vs 71%). Anovel finding of this analysis was that the renal excretion of the DCEmetabolites was also induced. Conclusions. This population PK-MB model for (R,S)-IFF may beuseful in the optimization of patient care, and gives new insight intothe metabolism of (R,S)-IFF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007561727948
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    Paper (German National Licenses)
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