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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Study of a Novel Amphotericin B Colloidal Dispersion with Improved Therapeutic Index (1991)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 618 (1991), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1991.tb27282.x
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  • 2
    Electronic Resource
    Electronic Resource
    Comparative Tissue Distribution and Elimination of Amphotericin B Colloidal Dispersion (Amphocil®) and Fungizone® After Repeated Dosing in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 275-283 
    Details
    ISSN: 1573-904X
    Keywords: Amphotericin B ; Amphocil® ; Fungizone® ; Colloidal Dispersion ; Tissue Distribution ; Pharmacokinetics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic profiles of amphotericin B (AmB) after administration of Amphocil®, an AmB/cholesteryl sulfate colloidal dispersion (ABCD) and the micellar AmB/deoxycholate (Fungizone®) were compared after repeated dosing in rats. After administration of ABCD and Fungizone at an equal AmB dose (1 mg/kg), AmB concentrations in plasma and most tissues were lower for the ABCD dose, especially in the kidneys where reduced drug concentration correlated with reduced nephrotoxicity. In contrast, AmB concentrations in the liver were substantially higher when ABCD was administered; however, without an accompanying increase in hepato-toxicity. Daily administration of ABCD for 14 days did not lead to AmB accumulation in plasma; while a slight accumulation was observed after multiple administration of Fungizone. AmB was eliminated more slowly from the plasma and various tissues and urinary and fecal recoveries of AmB were reduced after ABCD administration. These results suggest that ABCD may be stored in tissues in a form that is less toxic and is eliminated from the systemic circulation by a different mechanism than the free and protein-bound AmB in plasma. AmB accumulation in the spleen was observed when higher doses of ABCD (5 mg/kg) were administered, which could be due to saturation of hepatic uptake of AmB. Comparison of spleen concentrations of AmB between ABCD and Fungizone® at 5 mg/kg AmB doses was not possible because of Fungizone's toxicity in rats. In all other organs, AmB concentrations reached or approached a steady state within two weeks of dosing with ABCD. Urinary and fecal clearances of AmB were not different between ABCD and Fungizone administration. In summary, the distribution and elimination characteristics of AmB in rats were substantially altered when it was administered as ABCD in comparison to Fungizone. Nephrotoxicity of AmB in rats was reduced after administration of ABCD apparently because of the altered tissue distribution pattern. Thus, ABCD (Amphocil®) may be a clinically beneficial formulation of AmB in patients with systemic fungal infections.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016243313027
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  • 3
    Electronic Resource
    Electronic Resource
    Altered Tissue Distribution and Elimination of Amikacin Encapsulated in Unilamellar, Low-Clearance Liposomes (MiKasome®) (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1775-1781 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; aminoglycosides ; amikacin ; MiKasome ; tissue distribution ; elimination/excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amikacin in small unilamellar liposomes (MiKasome®) has prolonged plasma residence (half-life 〉 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system. Methods. Rats received one intravenous dose (50 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile. Results. Liposomal amikacin increased and prolonged drug exposure in all tissues. Tissue half-lives (63−465 hr) exceeded the plasma half-life (24.5 hr). Peak levels occurred within 4 hours in some tissues, but were delayed 1−3 days in spleen, liver, lungs and duodenum, demonstrating the importance of characterizing the entire tissue concentration vs. time profile for liposomal drugs. Predicted steady-state tissue concentrations for twice weekly dosing were 〉100 μg/g. Less than half the liposomal amikacin was recovered in tissues and excreta, suggesting metabolism occurred. Amikacin was not detected in plasma ultrafiltrates. Tissue-plasma partition coefficients (0.2-0.8 in most tissues) estimated from tissue-plasma ratios at Tmax were similar to those estimated from tissue AUCs. Conclusions. Low-clearance liposomal amikacin increased and prolonged drug residence in all tissues compared to conventional amikacin. The long tissue half-lives suggest liposomal amikacin is sequestered within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011925132473
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  • 4
    Electronic Resource
    Electronic Resource
    Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1694-1701 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018997730462
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  • 5
    Electronic Resource
    Electronic Resource
    Safety, Toxicokinetics and Tissue Distribution of Long-Term Intravenous Liposomal Amphotericin B (ambisome®): A 91-day Study in Rats (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1494-1502 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; toxicokinetics ; tissue distribution ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels 〉200 μg/ml and tissue levels 〉3000 μg/g.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007605024942
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  • 6
    Electronic Resource
    Electronic Resource
    Time-dependent, plasma-sulfate-independent kinetics of salicylamide in dogs (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 151-159 
    Details
    ISSN: 1573-8744
    Keywords: salicylamide ; nonlinear metabolism ; sulfoconjugation ; phenolic drugs ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The mechanisms of the dose-dependent elimination kinetics of salicylamide in dogs were examined. Salicylamide was infused continuously over three consecutive 90-min periods. The rates of infusion during Periods I and III were the same. During Period II the infusion rate was 2.5-fold higher. Plasma concentrations of inorganic sulfate were kept constant by the administration of exogenous sulfate. The plasma concentrations of salicylamide, which reached steady state during Period I but not during II or III, were twice as high at the end of Period III than those at the end of Period I. Typical Michaelis-Menten kinetics do not explain these results. When salicylamide was given as 40 mg/kg single oral dose, clearance of an intravenous tracer dose of radiolabeled salicylamide was greatly reduced within 10 min but returned to baseline values by 240 min after the oral dose, despite persistently low plasma concentrations of inorganic sulfate. Therefore, dose- and time-dependent factors other than Michaelis-Menten kinetics, depletion of inorganic sulfate concentrations, and rate limitation of supply of “active sulfate” from plasma inorganic sulfate stores produce the dose- and time-dependent kinetics of salicylamide in the dog. Product inhibition of salicylamide sulfoconjugation remains a possible explanation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062257
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  • 7
    Electronic Resource
    Electronic Resource
    Factors Affecting the Release Rate of Terbutaline from Liposome Formulations After Intratracheal Instillation in the Guinea Pig (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 220-223 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; bronchodilators ; bioavailability ; intratracheal instillation ; pulmonary absorption ; terbutaline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Maximum duration of bronchodilator efficacy in inhaled liposome-based formulations depends on optimizing the in vivo release rate of the encapsulated bronchodilator. We investigated the effect of several formulation variables on the pulmonary residence time of 3H-terbutaline sulfate liposomes administered intratracheally in guinea pigs, using an improved method enabling the measurement of pulmonary drug absorption for extended periods of time in conscious animals. Half-lives of liposome-encapsulated 3H-terbutaline disappearance from the lungs and airways after instillation ranged from 1.4 to 18 hr and were markedly affected by liposome size, cholesterol content, and phospholipid composition. This study demonstrates that liposomes can significantly prolong the residence time of bronchodilators in the lungs and that precise control over the pulmonary residence time of encapsulated bronchodilators can be achieved by controlling formulation variables.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018989423909
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