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Purpose: To evaluate distribution kinetics of drugs by the relative dispersion of disposition residence time and demonstrate its uses, interpretation and limitations., Materials and Methods: The relative dispersion was estimated from drug disposition data of inulin and digoxin fitted by three-exponential functions, and calculated from compartmental parameters published for fentanyl and alfentanil. An interpretation is given in terms of a lumped organs model and the distributional equilibration process in a noneliminating system., Results: As a measure of the deviation from mono-exponential disposition (one-compartment behavior), the relative dispersion provides information on the distribution kinetics of drugs, i.e., diffusion-limited distribution or slow tissue binding, without assuming a specific structural model. It also defines the total distribution clearance which has a clear physical meaning., Conclusion: The residence time dispersion is a model-independent measure that can be used to characterize the distribution kinetics of drugs and to reveal the influence of disease states. It can be estimated with high precision from drug disposition data.

Purpose: The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl-beta-cyclodextrin (Me(beta)CD) for controlled drug release., Methods: A hydrophilic model molecule, inulin, was encapsulated within positively charged and PEG-ylated liposomes and its release was measured in the presence of Me(beta)CD after vesicle dispersion within the bioadhesive Carbopol 974P gel. Freeze-fracture electron microscopy (FFEM) was used to follow liposome morphological changes when dispersed within the hydrogel. Liposome-Me(beta)CD interactions were investigated by turbidity monitoring during continuous addition of Me(beta)CD to liposomes and by FFEM., Results: Inulin diffusion within the gel was influenced by Carbopol 974P concentration since no gel erosion occurred. When dispersed within the gel, positively charged liposomes displayed a higher stability than PEG-ylated vesicles. In the presence of Me(beta)CD, higher amounts of free inulin were released from liposomes, especially in Carbopol-free system. Me(beta)CD appeared to diffuse towards lipid vesicles and permeabilized their bilayer allowing inulin leakage. Indeed, freeze-fracture experiments and liposome turbidity monitoring have shown that Me(beta)CD behaved as a detergent behavior, resulting in lipid vesicle solubilization., Conclusion: is able to mediate, within a bioadhesive hydrogel, the release of a liposome-encapsulated molecule allowing further application of this delivery system for mucosal administration.

Purpose: To characterize methacrylated inulin hydrogels with respect to their release properties., Methods: Proteins (bovine serum albumin or lysozyme) were used as model drugs and were loaded during or after hydrogel formation. Parameters such as the drug loading method, the molecular weight of the proteins, the initial drug loading concentration, the hydrogel feed composition, degree of substitution, and size of the hydrogel were investigated by determining the release of the model proteins from the hydrogels in a phosphate buffer solution. The biodegradable properties were investigated by studying the release of bovine serum albumin in a solution of inulinase., Results: In vitro protein release from methacrylated hydrogels was influenced by factors such as the drug loading procedure and the molecular weight and loading concentration of the proteins. The feed composition and degree of substitution of inulin seem to be crucial in controlling both the extent and the rate of release. Protein release was clearly enhanced in the presence of inulinase, indicating the biodegradable properties of methacrylated inulin hydrogels., Conclusions: Several hydrogels show interesting properties with respect to the development of a colon-specific drug delivery system.

Purpose: The aim of this study was to evaluate the ability of an in vitro method of tissue distribution to accurately predict total water and extracellular aqueous spaces using marker compounds urea and inulin., Methods: Slices (50-200 mg) of all the major tissues in the rat were incubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and 3H-inulin for 2 h at 37 degrees C. Tissue weight was noted before and after incubation and the tissue-to-buffer ratios determined., Results: 14C-Urea Kp estimates were generally greater than total tissue water due to tissue swelling, which varied widely among the tissues, up to 41% in muscle. In most cases, Kp values were much closer to in vivo values after correcting for the 14C-urea in the imbibed media (Kpcorr). The method was able to distinguish between 14C-urea and 3H-inulin Kp values and indicated that inulin occupied a smaller space than urea, which for the majority of tissues corresponded to the extracellular space., Conclusions: The Kp(corr) values for 14C-urea and Kp for 3H-inulin were consistent with total tissue water and extracellular space for the majority of tissues studied, indicating their suitability as marker compounds for checking the viability of this in vitro method for estimating tissue distribution.

Purpose: The transepithelial transport of levofloxacin was evaluated in the isolated perfused kidney to investigate its renal secretory mechanisms., Methods: Levofloxacin was instantaneously administered into the renal artery together with inulin and Evans blue-labeled albumin, and the single-pass dilution curves of the renal venous and urinary outflow were determined in the absence or presence of various compounds. Kinetic parameters were computed based on non-compartment moment analysis., Results: The ratio of fractional excretion to filtration fraction (FE/FF) for levofloxacin was 2.99 +/- 0.18, indicating the involvement of tubular secretion. In the presence of cimetidine and quinolones, the FE/FF of levofloxacin was significantly decreased and the transepithelial mean transit time (Tcell) of levofloxacin was prolonged. The Tcell showed a negative correlation with renal secretion of levofloxacin, while the volume of distribution of levofloxacin showed no correlation., Conclusions: Transport on the brush-border membrane plays a determining step in the renal secretion of levofloxacin, and cimetidine and quinolones interact with levofloxacin transport on the brush-border membrane.

Purpose: To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability., Methods: HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [14C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000)., Results: Cereport increased the HBMEC permeability to [14C]-inulin, but not to [3H]-dextran. The effect was transient, maximal at 15 min (i.e., 79.3% increase), and polarized to the basolateral membrane. An inverted U, dose-response curve was observed with active concentrations of Cereport from 0.01 to 0.5 nmol/L, the plateau maximal effect between 0.5 and 10 nmol/L, and loss of activity at the highest concentration, i.e., 20 nmol/L. Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 micromol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 micromol/L) enhanced by 31% (p < 0.05) the effect of 0.1 nmolL Cereport. Unlabeled Cereport displaced [125I]-bradykinin and/or [125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side., Conclusions: Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its effects can be further modulated through changes in cAMP and cGMP second messenger systems.

Purpose: The relationship between rat intestinal permeability (Papp) of a range of hydrophilic probe molecules and probe geometry was examined., Methods: Molecules studies included mannitol, the polyethylene glycols (PEGs) 400, 900, and 4000, the dextran conjugated dye Texas Red (MW 3000) and the polysaccharide inulin (MW 5500). Molecular surface area, volume and cross-sectional diameter for each probe were determined from computer models. The effect of the bile salt sodium cholate, and bile salt: fatty acid mixed micelles on probe intestinal permeability was also studied., Results: Of the size parameters tested, cross-sectional diameter correlated best with log intestinal permeability. The data was fitted to a relationship of the form Papp = Papp zero exp(-Krca) where rca is the molecular cross sectional radius. Papp zero and K are constants. Estimates of equivalent pore radii (R) were also made; the use of rca giving the most reasonable estimate of R. Absorption of all probes was enhanced by both simple and mixed micellar systems., Conclusions: For large hydrophilic probes and possibly protein drugs, cross sectional diameter is a more important size parameter than volume based values for evaluating size-related retarded absorption. The relationship established may be used as a tool to assess absorption enhancement potential of excipients.

Purpose: To clarify the role of the kidney in the elimination of a recombinant human granulocyte colony-stimulating factor, nartograstim, we have investigated its pharmacokinetics in rats with renal failure., Methods: The steady-state clearance (CLss) were determined by the intravenous infusion for 4 hr to unilateral renally-ligated and cisplatin-treated rats, whose renal functions were about 50 and 10% of controls, respectively., Results: CLss of nartograstim (27 ml/hr/kg) in the renally-ligated rats at a high infusion rate was significantly lower (25%) than in control rats (p < 0.05). CLss in these rats, at a low infusion rate was 95 ml/hr/kg, 14% lower than in control rats. The saturable CLss in these rats, 68 ml/hr/kg, was not significantly different from control rats (75 ml/hr/kg, p > 0.05). Also, CLss in cisplatin-treated rats with extensive renal failure, at a high infusion rate, decreased to 57% of controls. Furthermore, the total body clearances (CLtot) of nartograstim after bolus intravenous administration to renally-ligated and cisplatin-treated rats were reduced to 33-49% of controls., Conclusions: These results suggest that the kidney may be responsible for 40-50% of the nonsaturable clearance of nartograstim. Thus, the kidney should make a major contribution to the elimination of nartograstim when rats are given a high dose of nartograstim, which saturates the receptor-mediated clearance.

Two strains of Madin Darby canine kidney (MDCK) cells were grown on a polycarbonate membrane with 3-micron pores without any extracellular matrix treatment. The membrane, 2.45 cm in diameter, which is part of a commercially obtained presterilized culture insert, provides two chambers when placed in a regular six-well culture plate. This device was found to be convenient for investigating transport of a few selected fluid-phase markers across the MDCK cell monolayer. Both the strain from the American Type Culture Collection (ATCC) and the so-called highly resistant strain I, at a serial passage between 65 and 70, showed a seeding concentration-dependent lag phase followed by a growth phase with a 21-hr doubling time. When seeded at 5 x 10(4) cells/cm2, cell confluence was achieved in 5 days in a modified Eagle's minimum essential medium (MEM) containing 10% fetal bovine serum under a 5% CO2 atmosphere. Similarly, transepithelial electrical resistance (TEER) also reached a plateau value in 5 days. Both light and electron microscopic examinations revealed well-defined junctional structures. Transport of the fluid-phase markers, sucrose, lucifer yellow CH (LY), inulin, and dextran across the MDCK cell monolayers was studied primarily at 37 degrees C following the apical-to-basolateral as well as the basolateral-to-apical direction. Large variations in the steady-state transport rate were observed for a given marker between the cell layer preparations. Thus, the present study proposes an "internal standard" procedure for meaningful comparisons of the transport rate. When normalized to the rate of sucrose, the rate ratio was 1.00:0.80:0.67:0.15 for sucrose:LY:inulin:dextran.(ABSTRACT TRUNCATED AT 250 WORDS)