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  • 1
    Electronic Resource
    Electronic Resource
    Absorption of 2′, 3′-Dideoxyinosine from Lower Gastrointestinal Tract in Rats and Kinetic Evidence of Different Absorption Rates in Colon and Rectum (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 763-770 
    Details
    ISSN: 1573-904X
    Keywords: 2′, 3′-dideoxyinosine (ddI) ; didanosine ; anti-AIDS drug ; rectal infusion ; rectal bioavailability ; rectal and colonic absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study explored the rectal route of administration for 2′,3′-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-3H]ddI (20 µCi, equivalent to 2.1 µg), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 ± 2.2 µg/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 ± 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate–time profiles by the Loo–Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018928320449
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  • 2
    Electronic Resource
    Electronic Resource
    Percutaneous Absorption of 2′,3′-Dideoxyinosine in Rats (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 809-815 
    Details
    ISSN: 1573-904X
    Keywords: 2′,3′-dideoxyinosine ; transdermal ; bioavailability ; follicular density ; penetration enhancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study explored the topical route for administering of 2′,3′-dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (∼180 mg/kg) dispersed in ~1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [3H]ddI. At 24 hr, the experiment was terminated and skin sections at the application site were removed. After topical application, average plateau plasma levels of about 0.6 µg/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route for ddI. The effect of a mixture of penetration enhancers, Azone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. However pre-treatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr. In summary, the transdermal bioavailability of ddI exceeded the 15% oral bioavailability found in previous studies by more than 3 folds and was further increased by the pretreatment with absorption enhancers. These data indicate the topical route as an attractive administration route.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018965305234
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  • 3
    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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  • 4
    Electronic Resource
    Electronic Resource
    Proliferation Indices as Molecular Pharmacodynamic Endpoints in Evaluation of Anticancer Drug Effect in Human Solid Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1546-1551 
    Details
    ISSN: 1573-904X
    Keywords: proliferative indices ; molecular pharmacodynamic endpoints ; anticancer drugs ; human solid tumors ; thymidine ; bromodeoxyuridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The present study compared proliferative indices, i.e. incorporation of DNA precursor (i.e. thymidine or TdR, and bromodeoxyuridine or BrdU) and expression of proliferating cell nuclear antigen (PCNA), as molecular pharmacodynamic endpoints in evaluation of anticancer drug effect in human solid tumors. Methods. Tumor specimens obtained from patients were grown as histocultures. After treatment with doxorubicin, mitomycin C, and/or paclitaxel, cells labeled by [3H]TdR were identified using autoradiography, and cells labeled by BrdU and PCNA were identified using immunohistochemical techniques. Drug effect was measured as reduction of DNA precursor-labeled cells or PCNA-expressing cells. Results. The results indicate that (a) the two DNA precursors, TdR and BrdU, labeled the same cells and resulted in identical pharmacodynamics, (b) the pharmacodynamics established using inhibition of DNA precursor incorporation were qualitatively and quantitatively different from the pharmacodynamics established using inhibition of PCNA expression, (c) the inhibition of PCNA expression was erratic in some tumors, and (d) the differences in pharmacodynamics established using the two end points are drug-specific, with greater differences for paclitaxel than for mitomycin C. Conclusions. The erratic results measured by the PCNA labeling method suggest that this method may be less reliable than the conventional DNA precursor labeling method. The finding of identical pharmacodynamics of doxorubicin and paclitaxel established using BrdU and [3H]TdR indicates that the two precursors are interchangeable. Because the methodology for detecting BrdU incorporation requires less time and does not require the use of radioactivity, we conclude that inhibition of BrdU incorporation represents a useful endpoint for evaluating the antiproliferative activity of anticancer drugs in human solid tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011998932047
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  • 5
    Electronic Resource
    Electronic Resource
    Extensive Absorption of 2′,3′-Dideoxyinosine by Intratracheal Administration in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1901-1906 
    Details
    ISSN: 1573-904X
    Keywords: drug therapy ; AIDS ; intratracheal intubation ; biological availability ; animal studies ; 2′,3′-dideoxyinosine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the intratracheal route of administration as an alternative to oral administration for 2′,3′-dideoxyinosine (ddI). Methods. A ddI dose (40 mg/kg/300 µl or 6.5 mg/kg/50 µl) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 µg/kg) of 3H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. Results. ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 µL dose spilled over to the gastrointestinal tract, where the entire 50 µL dose was retained in the lungs. The different distribution of the two doses/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes. Conclusions. These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016283604540
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  • 6
    Electronic Resource
    Electronic Resource
    Apoptosis: A New Pharmacodynamic Endpoint (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1659-1671 
    Details
    ISSN: 1573-904X
    Keywords: apoptosis ; programmed cell death ; drug induced apoptosis ; pharmacodynamic endpoint
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012159208559
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  • 7
    Electronic Resource
    Electronic Resource
    Differential Effect of Taxol in Rat Primary and Metastatic Prostate Tumors: Site-Dependent Pharmacodynamics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1305-1312 
    Details
    ISSN: 1573-904X
    Keywords: taxol ; pharmacodynamics ; rat MAT-LyLu prostate tumors ; primary and metastatic tumors ; apoptosis ; p-glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study compared the sensitivity of rat prostate MAT-LyLu primary and lymph node metastatic tumors to taxol. Methods. Tumors were established by subcutaneous implantation of tumor cells in a hind leg (primary site) of male Copenhagen rats. Lymph node metastases were used for serial transplantation. Eleven pairs of primary and metastatic tumors between the sixth and twentieth generations were harvested and maintained as 3-dimensional histocultures. The effects of taxol (24 hr treatment at 1 nM to 10 µM) were measured by the appearance of apoptotic cells, and by the inhibition of DNA precursor (thymidine) incorporation. To determine the basis of differential sensitivity of primary and metastatic tumors to the DNA inhibition, we examined the expression of multidrug resistance p-glycoprotein (Pgp) and the accumulation of 3H-taxol after 24 hr exposure and the retention after a 48 hr washout period. Results. The fraction of apoptotic cells increased linearly with the logarithm of taxol concentration to a maximal value of 25%; the concentration-response curves for primary and metastatic tumors were superimposable. Taxol produced a sigmoidal, concentration-dependent inhibition of thymidine incorporation; the maximal inhibition of ~40% was reached at 0.1 and 1 µM for primary and metastatic tumors, respectively. Within the primary or metastatic subgroups, the IC30 (drug concentration that produced a 30% inhibition of DNA synthesis) among consecutive generations varied by 〈 5 fold, but the primary tumor consistently showed a lower IC30 than the daughter or the parent metastatic tumor (mean, 20-fold; median, 15-fold; range, 6- to 56-fold). The finding that the lower drug sensitivity in metastatic tumors was not exhibited in its daughter primary tumor but was regained in its daughter metastatic tumors suggests that the chemoresistant phenotype is maintained only in lymph nodes and not in the primary site. There were no differences in the Pgp status (neither tumor expressed Pgp), accumulation and retention of taxol in primary and metastatic tumors. Conclusions. Taxol induced apoptosis and inhibited DNA synthesis in the rat MAT-LyLu primary and lymph node metastatic tumors. The apoptotic effect was not different among the two tumors, whereas the primary tumor was more sensitive to the inhibition of DNA synthesis. The differential sensitivity of the two tumors to the DNA effect is not associated with a difference in Pgp expression, drug accumulation nor drug retention, and appears to be associated with changes that are linked to lymph node metastasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016053412582
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  • 8
    Electronic Resource
    Electronic Resource
    Penetration Kinetics of 2′,3′-Dideoxyinosine in Dermis Is Described by the Distributed Model (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 108-112 
    Details
    ISSN: 1573-904X
    Keywords: percutaneous penetration kinetics ; 2′,3′-dideoxyinosine ; distributed model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present study evaluated the kinetics of drug penetration in the dermis. A rat was given a dermal dose of 2′,3′-dideoxyinosine (ddI). At 6 hr, the skin tissue was excised, immediately frozen and sectioned, and the decline of drug concentration as a function of tissue depth was determined. The tissue concentration-depth profile showed a semilogarithmic decline, as would be expected in a distributed tissue kinetic model which incorporates diffusion and capillary membrane transport. The goodness of fit of the profiles by the simple diffusion and the distributed models were compared using four statistical criteria, i.e., coefficient of determination, Akaike Information criterion, Schwartz criterion and Imbimbo criterion. These analyses showed that the decline of tissue concentration versus tissue depth in the dermis was better described by the distributed model than by the diffusion model in all 7 animals. To examine the effect of blood perfusion on the tissue concentration-depth profiles, some of the tissues were frozen after 1 and 2 hr storage at room temperature. In contrast to the adjacent tissues frozen immediately, the concentration-depth profiles in tissues frozen after a 1-2 hr delay were described equally well by distributed and diffusion models. A comparison of the concentration-depth profiles in the tissues processed immediately or after a delay showed a 7 fold more shallow slope and a 60% lower concentration at the epidermis-dermis interface after storage. However, storage did not alter the total amount of drug in the entire dermis. Drug degradation during storage was further ruled out by the insignificant ddI degradation in 10% skin homogenate (a half-life of ~70 hr). These results indicate that under in vitro conditions, where there is no blood flow to remove the drug, the kinetics of drug penetration in the dermis are described by simple diffusion in accordance with the concentration gradient. In summary, these data indicate the importance of capillary blood flow on drug penetration profiles in the dermis, and that concentration-depth profiles in the dermis is described by the distributed model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016298906589
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  • 9
    Electronic Resource
    Electronic Resource
    Use of Drug Kinetics in Dermis to Predict in VivoBlood Concentration After Topical Application (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 2012-2017 
    Details
    ISSN: 1573-904X
    Keywords: 2′,3′-dideoxyinosine ; distributed model ; cutaneous absorption ; prediction of in vivo plasma concentration ; animal study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To use the drug kinetics in dermis to predict the in vivo blood concentration after topical administration. Methods. A two-step pharmacokinetic model was established. The first step was to calculate the drug input rate or flux from the skin to the systemic circulation using the drug kinetic parameters in dermis. These parameters include (a) distance over which the drug concentration declines by 50%, (b) drug concentration at the epidermal-dermal junction, and (c) minimal plateauing drug concentration in the muscle layer. These parameters were experimentally determined from the drug concentration-tissue depth profiles in the dermis, after the application of a topical dose of ddI (200 mg/kg) to rats. The second step was to use the drug input rate together with the systemic disposition pharmacokinetics of ddI in rats to predict the plasma concentration-time profiles. The model-predicted plasma concentration-time profiles were compared with the observed profiles, to determine the validity of the proposed pharmacokinetic model. Results. The observed steady state concentration (Css) in individual animals (n = 6) deviated from the predicted values by 3 to 55% with 3 of 6 rats showing a 〈15% deviation. The mean observed Css of all animals deviated from the mean predicted values by less than 15%. Conclusions. The close agreement between the observed and the model-predicted drug concentrations indicates that the systemic drug input can be calculated from the drug kinetics in the dermis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016268628647
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  • 10
    Electronic Resource
    Electronic Resource
    Different pH Dependency of Mitomycin C Activity in Monolayer and Three-Dimensional Cultures (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1887-1891 
    Details
    ISSN: 1573-904X
    Keywords: mitomycin C ; pH effect ; human bladder cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Previous studies by other investigators have shown an enhancement of mitomycin C (MMC) activity at acidic extracellular pH (pHe) in monolayer cultures of human cells. The goal of the present study was to determine if the efficacy of intravesical MMC therapy in patients treated for superficial bladder cancer can be enhanced by using acidified dosing solutions. We evaluated (a) the effect of pHe on MMC activity in patient bladder tumors in vitro, and (b) the pH dependency of MMC activity in 2-dimensional monolayer and 3-dimensional multilayer cultures of human bladder RT4 tumor cells. Methods. Patient bladder tumors were maintained as 3-dimensional histocultures. RT4 cells were harvested and maintained as monolayer cultures or as 3-dimensional cell pellets on a collagen gel matrix. The cell pellets were 300–450 cell layers and 4,000–5,000 µm in diameter. Tumors or cells were incubated for 2 hr with MMC-containing media at pHeof 5, 6, and 7.4. The drug effect was measured by the inhibition of DNA precursor (thymidine) incorporation. The stability of MMC as a function of pHe was determined. About 24% of MMC was degraded following 2 hr exposure at pHe 5 and ≤ 2% at pHe 6 and 7.4. Results. The drug concentrations required to inhibit thymidine incorporation by 50% (IC50) were corrected for the degraded MMC at acidic pHe. The results showed no pH-dependent MMC activity in human patient bladder tumors nor in RT4 multilayer cultures; the IC50 values were about 10 µg/ml at all three pHe. In contrast, the monolayer RT4 cultures showed a pH-dependent MMC cytotoxicity; the IC50 were 0.1, 0.8 and 1.2 µg/ ml at pHe 5,6 and 7.4, respectively (p 〈 0.05). Pre-incubation of multi-layered RT4 cultures in acidic pH medium for 8 hr enhanced the MMC activity; the IC50 was reduced by about 5 fold at pHe 5 and about 3 fold at pHe 6. Similar pH-dependent MMC activity was found when multilayers were pre-treated for 1 hr with 0.5 µml nigericin, a proton ionophore known to cause the intracellular pH (pHi) to equilibrate with pHe. Conclusions. These data suggest that the difference in the pH dependency of MMC activity in the monolayer and multilayer systems was due to the different experimental conditions. The time lag for pHi to equilibrate with pHe in the multilayer systems and the instability of MMC at low pHe imply that the efficacy of intravesical MMC therapy is unlikely to be enhanced by using acidic dosing solution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016053729362
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