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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacology of N,N-di(n-butyl)adriamycin-14-valerate in the rat (1996)
    Springer
    Cancer chemotherapy and pharmacology 37 (1996), S. 472-478 
    Details
    ISSN: 1432-0843
    Keywords: Key words N-Benzyladriamycin-14-valerate ; Pharmacology ; Anthracycline analogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Lipophilic N-alkylanthracyclines such as AD 198 (N-benzyladriamycin-14-valerate) or AD 201 [N,N-di-(n-propyl)adriamycin-14-valerate], which exert their cytotoxicity through mechanisms which are not yet fully defined, possess inherent abilities to circumvent multidrug resistance in vitro and in vivo, possibly through alterations in normal intracellular drug trafficking. As part of structure-activity studies with this class of agent, we have now examined the pharmacology of AD 202 [N,N-di(n-butyl)adriamycin-14-valerate], another analog possessing superior antitumor activity to doxorubicin in vivo and an ability to circumvent multidrug resistance in vitro. Following the administration of AD 202 (20 mg/kg, i.v.) to anesthetized rats, rapid drug distribution (T1/2 5 min) was followed by more gradual elimination (T1/2 3.6 h). Plasma clearance of AD 202 (224±63.6 ml/min per kg) and steady state volume of distribution (25.7±11.1 l/kg) were indicative of extensive tissue sequestration and/or a large degree of extra-hepatic metabolism. The parent drug predominated in plasma until 20 min, thereafter N,N-di(n-butyl)adriamycin became the principal circulating anthracycline. The systemic exposure to this biotransformation product (area under the plasma concentration-time curve from time zero to 480 min AUC0-480 28 1672 ng ⋅ min/ml) was 〉tenfold higher than for the other detected plasma products (N-butyladriamycin-14-valerate, N-butyladriamycin, and three unidentified fluorescent signals; P1-3). Total urinary elimination over 8 h was limited (1.9% of dose), occurring predominantly as N,N-di(n-butyl)adriamycin (1.2% of dose), N-butyladriamycin (0.4% of dose), and their corresponding 13-carbinol metabolites (〈0.1% of dose each). Low levels of adriamycin (ADR), aglycones and two unidentified products were also seen. Parental AD 202 was found in urine only up to 1 h. By contrast, hepatic elimination of parent drug was seen, albeit at low levels, through 8 h. Excretion by this route (22% of dose) occurred principally as N-butyladriamycin (8% of dose), N-butyladriamycinol (2.1% of dose) with lower levels of N,N-di(n-butyl)adriamycin (1.6% of dose), N,N-di(n-butyl)adriamycin (0.8% of dose), and aglycones (4.3% of dose, combined). Other products included ADR (1.1% of dose) and two unidentified signals (3.4% of dose, combined). The relatively poor mass balance in these studies is attributed to prolonged intracellular retention (elimination T1/2 24.2 h) of N,N-di(n-butyl)adriamycin. Thus, in common with other N-alkylanthracyclines, the pharmacology of AD 202 is complex but its therapeutic properties clearly are not derived from an ADR prodrug effect. Significant differences continue to be noted as to the metabolic fate of congeners of this class of anthracycline analogs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050414
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  • 2
    Electronic Resource
    Electronic Resource
    Creation of Polarized Cells Coexpressing CYP3A4, NADPH Cytochrome P450 Reductase and MDR1/P-glycoprotein (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 803-810 
    Details
    ISSN: 1573-904X
    Keywords: CYP3A4 ; Pgp ; Caco-2 ; LLC-PK1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop model polarized cell systems expressingcytochrome P4503A4, NADPH P450 reductase, and P-glycoprotein (Pgp). Methods. LLC-PK1 and derivative L-MDR1 cells stably expressing Pgp,the product of the multidrug resistance gene (MDR1), were transfectedstably using either a mammalian neomycin selectable expression vector(CYP3A4-Neo) or an episomal vector based on Epstein—Barr virus(CYP3A4-Hygro). These CYP3A4 expressing cells were compared withLLC-PK1, L-MDR1, or Caco-2 cells transduced with Adenovirus-3A4vector (Ad3A4) with or without simultaneous Adenovirus-P450 Reductase(AdRed) transduction. Cells were characterized for expression of CYP3A4protein and CYP3A4 mediated metabolism towards midazolam and testosterone. Analysis of membrane integrity and drug transport assays wereperformed to determine whether infection with recombinant Ad3A4 ±AdRed affected Pgp function. Results. The rank order of optimal CYP3A4 expression and activitiesin LLC-PK1 and L-MDR1 cells from highest to lowest was cellsco-transduced with Ad3A4 plus AdRed 〉〉 Ad3A4 〉〉〉CYP3A4-Hygro 〉 CYP3A4-Neo. Similarly, coexpression of Ad3A4 plus AdRedled to enhanced CYP3A4 mediated metabolism in Caco-2 cells overcells with Ad3A4 alone. Incubation of transwell cultured cells expressing Ad3A4/AdRed with midazolam led to readily detectable metabolitein the medium. In microsomes from Caco-2 and LLC-PK1 cells, eachco-transduced with Ad3A4/AdRed, Vmax values for testosterone6β-hydroxylase activity ranged from 414 to 1350 pmoles/min/mg,respectively. For either Caco-2 or LLC-MDR1 cells, TEER values and therate of apical to basal and basal to apical transport of vinblastine ordigoxin were similar in cells with and without Ad3A4/Red transduction. Conclusions. Polarized cellular systems coexpressing Ad3A4, AdRed,and the MDR1/Pgp transporter were developed and characterized. Theresults document the utility of these polarized model systems forsimultaneous drug transport/drug metabolism studies. Since the experimentalapproach can be adapted to study the interplay of multipleenzyme/transporting systems, it may find significant application as a screeningtool for the pharmaceutical industry and as a more basic research toolto study the kinetics of intestinal drug bioavailability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007599923694
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Aminolevulinic Acid After Intravesical Administration to Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 288-295 
    Details
    ISSN: 1573-904X
    Keywords: aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018840827910
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of bladder resorption on pharmacokinetic data analysis (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 183-205 
    Details
    ISSN: 1573-8744
    Keywords: bladder resorption ; renal clearance ; computer simulations ; bladder recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (k a), interval between bladder voiding (Δt void),ratio of renal elimination rate constant to overall elimination rate constant (k ex:k el ratio), andk el ort 1/2. The data identifiedk a, Δt void, andk ex:k el ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values ofk a, Δt void, andk ex:k el ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CL renal), total body clearance (CL total), nonrenal clearance (CL nonrenal),t 1/2, mean residence time (MRT), amount and fraction of dose excreted in urine (A ex andf e), and volume of distribution at steady state (Vd ss). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plama concentration-time profile,MRT andt 1/2, but decreasedCL renal,CL total,A ex, andf e.Vd ss was relatively unchanged. Overestimation of MRT andt 1/2 was dependent onk a,k ex:k el ratio,and Δt void. Underestimation inCL renal,A ex, andf e was not dependent on thek ex:k el ratio, but was affected by changes ink a and Δt void.CL renal andf e were the most sensitive pharmacokinetic parameters, with a≥50% underestimation at ak a value that we reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over-or underestimation in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353328
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  • 5
    Electronic Resource
    Electronic Resource
    A Method to Study Drug Concentration–Depth Profiles in Tissues: Mitomycin C in Dog Bladder Wall (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 168-173 
    Details
    ISSN: 1573-904X
    Keywords: tissue concentration profile ; bladder wall ; dog ; mitomycin C
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Determination of the depth of penetration of locally applied drug therapy and evaluation of possible mechanisms of drug transport require knowledge of drug concentration-versus-tissues depth profiles. A method to determine the drug concentration–depth profile is needed. We have devised such a method and used it to determine the penetration of mitomycin C (MMC) in the dog bladder wall after intravesical drug instillation. This method is based on sectioning of frozen tissue into 40-µm segments, followed by drug extraction and high-pressure liquid chromatography analysis. Tissue concentrations could be detected with a sensitivity of 1 ng/sample, or 20 ng/g for tissue samples of approximately 2 × 2 cm. This sensitivity was sufficient to describe the penetration of MMC in the bladder wall of dogs, using an identical instillation technique, dwell time, and MMC concentration as in human patients. Tissue concentrations were expressed relative to tissue weight or tissue protein contents. For MMC, standardization to tissue weight yielded a better mathematical fit of the concentration-versus-depth profiles than standardization to protein content. The time interval between tissue harvesting and freezing was critical. The MMC concentration at the urothelial side of dog bladders was 2- to 10-fold higher in samples processed immediately after harvesting, compared to samples processed after 1 hr or longer. This significant decrease was not due to drug metabolism in situ. In separate in vitro experiments, we found that the degradation of MMC in 8% tissue homogenate was relatively slow, with only a 30% decline in concentration over 24 hr. We speculate that the decrease in concentration was due to passive diffusion of MMC, away from the urothelial side. In summary, the present study demonstrates that determination of drug penetration into tissues in vivo is feasible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015827700904
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