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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
    Histocultures of Patient Head and Neck Tumors for Pharmacodynamics Studies (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1493-1499 
    Details
    ISSN: 1573-904X
    Keywords: chemosensitivity ; histoculture ; head and neck tumors ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This investigation was to establish a clinically relevant experimental model to evaluate the pharmacodynamics of drugs used for head and neck cancers. A total of 83 surgical samples of primary and lymph nodal metastatic tumors was obtained from 66 patients. Fragments of these tumors were cultured on a collagen gel matrix. The tumor cell labeling index (LI) was determined by [3H]thymidine incorporation and autoradiography. Seventeen tumors (20%) were contaminated. About 80% of the remaining 65 tumors were successfully cultured for at least 2 weeks. The cultured tumor fragments retained the morphology and architecture of the freshly removed specimens; both tumor and stromal cells were present. The tumor cell LI after 2–3 weeks in culture, determined from the most proliferative area of the tissue, averaged 77 ± 12% for primary tumors and 78 ± 12% for nodal metastases. The activity of three clinically active agents, 5-fluorouracil (FU), cisplatin (DDP), and mitomycin C (MMC), was evaluated in 47 tumors. All three drugs inhibited the tumor LI. The concentrations needed to produce a 50% inhibition of the tumor LI (IC50) were within the clinically achievable concentration range. The intertumor variation in the IC50 for FU (60-fold) was considerably greater than that for DDP and MMC (7- to 8-fold). The nodal metastatic tumors appeared to be less sensitive to FU than the primary tumors, while there were no apparent differences for DDP or MMC. Tumors from patients previously treated with chemotherapy and/or radiotherapy appeared less sensitive to FU and DDP than tumors from untreated patients, but the differences were not statistically significant. Interestingly, tumors from previously treated patients were significantly more sensitive to MMC than tumors from untreated patients. The maintenance of the morphology of the fresh tumor and the observed intertumor variability in IC50 values indicate the preservation of intra- and intertumor heterogeneity in the histocultures. In summary the viability and high success rate of growth of human head and neck tumors in organ-like culture and the chemosensitivity of the cultured tumors to clinically active agents at clinically achievable concentrations support the use of this experimental model for pharmacodynamic evaluation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018935628085
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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
    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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  • 5
    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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  • 6
    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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  • 7
    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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  • 8
    Electronic Resource
    Electronic Resource
    Physiologically Based Pharmacokinetic Models of 2′,3′-Dideoxyinosine (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 337-344 
    Details
    ISSN: 1573-904X
    Keywords: ddI ; physiologic pharmacokinetic model ; tissue concentration ; pentamidine ; rat ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to develop physiologically based pharmacokinetic (PBPK) models for 2′,3′-dideoxyinosine (ddI) in rats when the drug was administered alone (ddI model) and with pentamidine (ddI + pentamidine model), and to use these models to evaluate the effect of our previously reported pentamidine-ddI interaction on tissue ddI exposure in humans. Methods. The PBPK models consisted of pharmacologically relevant tissues (blood, brain, gut, spleen, pancreas, liver, kidney, lymph nodes, muscle) and used the assumptions of perfusion-rate limited tissue distribution and linear tissue binding of ddI. The required physiologic model parameters were obtained from the literature, whereas the pharmacokinetic parameters and the tissue-to-plasma partition coefficients were calculated using plasma and tissue data. Results. The ddI model in rats yielded model-predicted concentration-time profiles that were in close agreement with the experimentally determined profiles after an intravenous ddI dose (5% deviation in plasma and 20% deviation in tissues). The ddI + pentamidine model incorporated the pentamidine-induced increases of ddI partition in pancreas and muscle. The two PBPK models were scaled-up to humans using human physiologic and pharmacokinetic parameters. A comparison of the model-predicted plasma concentration-time profiles with the observed profiles in AIDS patients who often received ddI with pentamidine showed that the ddI model underestimated the terminal half-life (t1/2,β) by 39% whereas the ddI + pentamidine model yielded identical t1/2,β and area-under-the-curve as the observed values (〈1% deviation). Simulations of ddI concentration-time profiles in human tissues using the two models showed that pancreas and lymph nodes received about 2- to 30-fold higher ddI concentration than spleen and brain, and that coadministration of pentamidine increased the AUC of ddl in the pancreas by 20%. Conclusions. Data of the present study indicate that the plasma ddI concentration-time profile in patients were better described by the ddI + pentamidine model than by the ddI model, suggesting that the pentamidine-induced changes in tissue distribution of ddI observed in rats may also occur in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012002206007
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Interaction Between Intravenous 2′,3′-Dideoxyinosine and Pentamidine in Rats (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 628-632 
    Details
    ISSN: 1573-904X
    Keywords: 2′,3′-dideoxyinosine ; pentamidine ; pharmacokinetic interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddl) and pentamidine. Background, ddl and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs. Methods. ddl (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay. Results. Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddl from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddl from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddl distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddl coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003). Conclusions. These data indicate that pentamidine increased the distribution of ddl into pancreas and muscle, whereas ddl increased the renal elimination of pentamidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016018726327
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of 2′,3′-dideoxyadenosine in dogs (1991)
    Springer
    Investigational new drugs 9 (1991), S. 159-168 
    Details
    ISSN: 1573-0646
    Keywords: 2′,3′-dideoxyinosine ; 2′,3′-dideoxyadenosine ; pharmacokinetics ; dogs ; AIDS ; cerebrospinal fuid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of 2′,3′-dideoxyadenosine (ddAdo) and 2′-3′-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (∼ 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3–11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites. Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 μg/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 μLg/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00175083
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