The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat

Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albu...

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Bibliographic Details
Published in:Pharmaceutical research 1991-03, Vol.8 (3), p.380-384
Main Authors: FRIJLINK, H. W, FRANSSEN, E. J. F, EISSENS, A. C, OOSTING, R, LERK, C. F, MEIJER, D. K. F
Format: Article
Language:English
Subjects:
2-Hydroxypropyl-beta-cyclodextrin
Animals
beta-Cyclodextrins
Biological and medical sciences
Blood Proteins - metabolism
Bones, joints and connective tissue. Antiinflammatory agents
Cyclodextrins - administration & dosage
Cyclodextrins - blood
Cyclodextrins - metabolism
Cyclodextrins - pharmacology
Flurbiprofen - administration & dosage
Flurbiprofen - blood
Flurbiprofen - pharmacokinetics
Injections, Intravenous
Male
Medical sciences
Naproxen - administration & dosage
Naproxen - blood
Naproxen - pharmacokinetics
Pharmacology. Drug treatments
Rats
Rats, Inbred Strains
Tissue Distribution
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Summary:Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1015857902238