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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Analysis of in Vivo Metabolism of Amino Acid or Dipeptide Conjugates of Salicylic Acid in Rabbit Intestinal Microorganisms (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 160-164 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetic analysis ; salicylic acid ; prodrug ; metabolism ; rabbit ; intestinal microorganism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We analyzed the pharmacokinetics of salicylic acid (SA)–amino acid (alanine, glutamic acid, methionine, and tyrosine) or SA−dipeptide (glycylglycine) conjugates in rabbits, by using a model that takes into account the metabolism of prodrug to SA by intestinal microorganisms and, also, by model-independent analysis. The blood concentration profiles of these prodrugs and released SA following intracecal and oral administration to rabbits were obtained previously (Nakamura et al., J. Pharm. Pharmacol., 44, 295–299, 1992; Chem. Pharm. Bull., 40, 2164–2168, 1992; Int. J. Pharm., 87, 59–66, 1992; J. Pharm. Pharmacol., 44, 713–716, 1992). First, the overall in vivo behavior was evaluated by statistical moment analysis. Next, the blood concentration profiles of prodrug and SA following intracecal and oral administration were simultaneously fitted to the above model. In general, good agreement was observed between fitted lines and experimental data for every prodrug, suggesting the validity of this model. The obtained parameters characterized the difference in the rate of metabolism and absorption among the prodrugs. Lower absorbability and enhanced hydrolysis rate of the prodrug lead to prolonged blood concentration of SA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018926618070
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  • 2
    Electronic Resource
    Electronic Resource
    Different Effects of Absorption Promoters on Corneal and Conjunctival Penetration of Ophthalmic Beta-Blockers (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1146-1150 
    Details
    ISSN: 1573-904X
    Keywords: beta-blocker ; drug delivery system ; ocular penetration ; absorption promoter ; eye
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to investigate the improvement in corneal penetration of ophthalmic beta-blockers of various lipophilicities afforded by absorption promoters and to compare the corneal against conjunctival penetration in response to absorption promoters. Methods. The penetration of the beta-blockers, atenolol, carteolol, tilisolol, timolol, and befunolol, in the presence of absorption promoters, across the isolated corneal and conjunctival membranes of albino rabbits was measured using a two-chamber glass diffusion cell. EDTA, taurocholic acid, capric acid, and saponin were used as the absorption promoters. Results. The absorption promoters significantly increased the corneal permeability of most beta-blockers, especially the hydrophilic agents. The absorption promoters also enhanced the conjunctival permeability of beta-blockers, although their effect in promoting conjunctival penetration was less than that on corneal penetration. There was a differing penetration of instilled beta-blockers in the cornea and conjunctiva in response to absorption promoters. Capric acid and saponin showed significant promoting action on corneal penetration, but not on conjunctival penetration. Taurocholic acid had a significant effect on conjunctival penetration but not on corneal penetration. Saponin caused slight irritation. Conclusions. Absorption promoters can improve the ocular delivery of beta-blockers and a selective use of absorption promoter can improve the extent and pathway of drug ocular absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016203725128
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  • 3
    Electronic Resource
    Electronic Resource
    Characterization of Ocular Pharmacokinetics of Beta-Blockers Using a Diffusion Model After Instillation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1596-1601 
    Details
    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018964823193
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  • 4
    Electronic Resource
    Electronic Resource
    Hepatic Disposition Characteristics of 111In-Labeled Lactosaminated Bovine Serum Albumin in Rats (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 1253-1257 
    Details
    ISSN: 1573-904X
    Keywords: lactosaminated bovine serum albumin ; liver targeting ; receptor-mediated endocytosis ; rat in vivo disposition ; constant infusion of the liver ; hepatocyte uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The hepatic disposition of lactosaminated bovine serum albumin (Lac-BSA) in rats was studied at the whole body, isolated liver, and isolated parenchymal cell levels. After intravenous injection, 111In-Lac-BSA (1 mg/kg) was rapidly eliminated from the plasma due to extensive uptake by liver parenchymal cells; however, a significant decrease in hepatic clearance was observed at high dose (50 mg/kg). In a single-pass, constant infusion experiment in the isolated liver, 111In-Lac-BSA was continuously extracted. The extraction ratio at steady state (Ess) for 111In-Lac-BSA was significantly decreased by coadministrating galactose, NH4Cl, or chloroquine, and at low temperature, suggesting that hepatic uptake of Lac-BSA proceeds via receptor-mediated endocytosis for asialoglycoprotein. Kinetic analysis of 111In-Lac-BSA binding with isolated parenchymal cells at 4°C yielded a dissociation constant (Kd) of 2.5 ×10−8M and a value of 3.5 × 105 maximal binding sites/cell (Bmax). The internalization rate constant (kint) for 111In-Lac-BSA was calculated to be 0.46 min−l in liver perfusion experiments using the EDTA-wash method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015895511208
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  • 5
    Electronic Resource
    Electronic Resource
    Hepatic Disposition Characteristics of Electrically Charged Macromolecules in Rat in Vivo and in the Perfused Liver (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 437-444 
    Details
    ISSN: 1573-904X
    Keywords: electric charge ; model macromolecule ; hepatic disposition ; cellular localization ; constant infusion ; adsorptive endocytosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of electric charge on the hepatic disposition of macromolecules was studied in the rat. Charged derivatives of dextran (T-70) and bovine serum albumin (BSA), mitomycin C–dextran conjugates (MMC-D), and lactosaminated BSA (Lac-BSA) were employed as model macromolecules. After intravenous injection, cationic macromolecules were rapidly eliminated from plasma because of their extensive hepatic uptake, while anionic and neutral macromolecules were slowly eliminated. Cationic macromolecules were recovered from parenchymal and nonparenchymal hepatic cells at a cellular uptake (per unit cell number) ratio of 1.4–3.2, while that of Lac-BSA was 14. During liver perfusion using a single-pass constant infusion mode, cationic macromolecules were continuously extracted by the liver, with extraction ratios at steady-state (E ss) ranging between 0.03 and 0.54, whereas anionic and neutral macromolecules were almost completely recovered in the outflow at steady state. The E ss for cationized BSA (Cat-BSA) and cationic MMC-Dcat were concentration dependent and decreased at low temperatures and in the presence of colchicine and cytochalasin B. The possible participation of the internalization process in the uptake of cationic macromolecules by hepatocytes was suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015886708598
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  • 6
    Electronic Resource
    Electronic Resource
    Statistical Moment Analysis of Hepatobiliary Transport of Phenol Red in the Perfused Rat Liver (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 140-146 
    Details
    ISSN: 1573-904X
    Keywords: phenol red ; rat liver perfusion ; hepatic uptake ; metabolism ; biliary excretion ; moment analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A new experimental system was applied to study hepatobiliary transport of drugs. Rat livers were perfused using a single-pass technique, and phenol red was momentarily introduced to this system from the portal side. Outflow dilution patterns of phenol red were analyzed using statistical moment theory, and kinetic parameters of hepatic distribution and elimination of phenol red were calculated from moments, namely, the hepatic extraction ratio (E i) and elimination rate constant (k el,i). A larger distribution volume (V i) was obtained for phenol red than for 131I-human serum albumin (HSA) and 51Cr-red blood cells (RBC), indicating its extravascular diffusivity. The biliary excretion of conjugated phenol red was delayed relative to that of the free agent. The larger biliary mean transit time (t bile,conj.) represents the processes of biliary transport and intrahepatic metabolism. Further, the effects of dose and perfusion temperature on the hepatobiliary transport of phenol red were determined. With high doses or low perfusion temperatures (20 and 27°C), E i, k el,i, and intrinsic clearance (CLint,i) of phenol red and biliary recovery of free and conjugated phenol red (F bile,free, F bile,conj) significantly decreased. The temperature-dependent and saturable processes in hepatic uptake, metabolism, and biliary excretion of phenol red were assessable to moment analysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015980525940
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