Abstract
Following intravenous administration, the uptake of colloidal drug carriers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenchymal cells and facilitate its biliary excretion and enterohepatic circulation. To test this hypothesis indomethacin was administered (10 mg/kg) in four groups of 10 rabbits each by intravenous infusion at a constant rate over 2 hr, either in its free form (aqueous solution) or as nanocapsules prepared from preformed poly(DL-lactide). Unchanged drug was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokinetic analysis led to the conclusion that the uptake of nanocapsules by liver macrophages reduces the concentration of the drug by enhancing its total clearance. This enhancement was due to an increase in biliary clearance, as a result of parallel increases in bile concentration and biliary excretion of the drug. It was also demonstrated that nanocapsules enhance the enterohepatic circulation of indomethacin.
Similar content being viewed by others
REFERENCES
K. J. Hwang. Liposomes pharmacokinetics. In M. J. Ostro (ed.), Liposomes: From Biophysics to Therapeutics, Marcel Dekker, New York, 1987, pp. 109–156.
R. L. Juliano. Factors affecting the clearance kinetics and tissue distribution of liposomes, microspheres and emulsions. Adv. Drug Deliv. Rev. 2:31–54 (1988).
S. Becker. Functions of the human mononuclear phagocyte system (a condensed review). Adv. Drug Deliv. Rev. 2:1–29 (1988).
N. Chiannilkulchai, N. Ammoury, B. Caillou, J.-Ph. Devissaguet, and P. Couvreur. Hepatic tissue distribution of doxorubicin-loaded nanoparticles after I.V. administration in reticulosarcoma M 5076 metastasis-bearing mice. Cancer Chemother. Pharmacol. 26:122–126 (1990).
N. Al-Khouri Fallouh, L. Roblot, H. Fessi, J.-Ph. Devissaguet, and F. Puisieux. Development of a new process for the manufacture of poly (isobutylcyanoacrylate) nanocapsules. Int. J. Pharm. 28:125–132 (1986).
W. P. Yu, G. M. Barratt, J.-Ph. Devissaguet, and F. Puisieux. Anti-metastatic activity in-vivo of MDP-I-alanyl-cholesterol (MTP-Chol) entrapped in nanocapsules. Int. J. Immunopharmacol. 13:167–173 (1991).
H. Fessi, F. Puisieux, J.-Ph. Devissaguet, N. Ammoury, and S. Benita. Nanocapsule formation by interfacial deposition following solvent displacement. Int. J. Pharm. 55:R1–R4 (1989).
N. Ammoury, H. Fessi, J.-Ph. Devissaguet, M. Allix, M. Plotkine, and R. G. Boulu. Effect on cerebral blood flow of orally administered indomethacin-loaded poly (isobutylcyanoacrylate) and poly(D,L-lactide) nanocapsules. J. Pharm. Pharmacol. 42:558–561 (1990).
N. Ammoury, H. Fessi, J.-Ph. Devissaguet, M. Dubrasquet, and S. Benita. Jejunal absorption, pharmacological activity, and pharmacokinetic evaluation of indomethacin-loaded poly(D,L-lactide) and poly(isobutylcyanoacrylate) nanocapsules in rats. Pharm. Res. 8:101–105 (1991).
N. Ammoury, M. Dubrasquet, H. Fessi, J.-Ph. Devissaguet, F. Puisieux, and S. Benita. Indomethacin loaded poly (D,L-lactide) nanocapsules: Protection from gastrointestinal ulcerations and antiinflammatory activity evaluation in rats. Clin. Mater., in press (1992).
K. Dietzel, W. S. Beck, H. Th. Schneider, G. Geisslinger, and K. Brune. The biliary elimination and enterohepatic circulation of ibuprofen in rats. Pharm. Res. 7:87–90 (1990).
C. Benveniste, R. Stribeni, and P. Dayer. Indirect assessment of the enterohepatic recirculation of piroxicam and tenoxicam. Eur. J. Clin. Pharmacol. 38:547–549 (1990).
D. E. Duggan, K. F. Hooke, R. M. Noll, and K. C. Kwan. Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem. Pharmacol. 25:1749–1754 (1975).
K. C. Kwan, G. O. Breault, E. R. Ummbenhauer, F. G. McMahon, and D. E. Duggan. Kinetics of indomethacin absorption, elimination and enterohepatic circulation in man. J. Pharmacokinet. Biopharm. 4:255–280 (1976).
M. A. Al-Meshal, Y. M. El-Sayed, A. A. Al-Angary, K. M. Lufti, and M. W. Gouda. Interruption of the enterohepatic circulation of indomethacin by cholestyramine in rabbits. Int. J. Pharm. 64:155–160 (1990).
Y. M. El-Sayed, M. A. Al-Meshal, A. A. Al-Angary, K. M. Lufti, and M. W. Gouda. Accelerated clearance of intravenous indomethacin by oral activated charcoal in rabbits. Int. J. Pharm. 64:109–115 (1990).
A. Drouet, M. Le Duff, R. Le Verge, and J.-Ph. Devissaguet. Application de la HPLC à l'étude de la clométacine chez l'homme. In J. M. Aiache and J. Hirtz (eds.), Proceedings 1st European Congress of Biopharmaceutics and Pharmacokinetics, Clermont-Ferrand, France, Vol. 2, 1981, pp. 502–507.
V. Andrieu, H. Fessi, M. Dubrasquet, J.-Ph. Devissaguet, F. Puisieux, and S. Benita. Pharmacokinetic evaluation of indomethacin nanocapsules. Drug Design Deliv. 4:295–302 (1989).
S. K. Cole, M. J. Story, T. Laudanski, M. Dwier, D. Attwood, J. Robertson, and S. G. Barnwell. Targeting drugs to the enterohepatic circulation: A potential drug delivery system designed to enhance the bioavailability of indomethacin. Int. J. Pharm. 80:63–73 (1992).
M. Cociglio, J. Bres, D. Sauvaire, R. Alric, and M. Richard. Pharmacokinetics of an indomethacin pro-drug: Apyramide after intravenous administration in dog. Eur. J. Drug Metab. Pharmacokin. 16:275–280 (1992).
P. Maincent, R. Le Verge, P. Sado, P. Couvreur, and J.-Ph. Devissaguet. Disposition kinetics and oral bioavailability of vincamine-loaded poly (alkylcyanoacrylate) nanoparticles. J. Pharm. Sci. 75:955–958 (1986).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fawaz, F., Bonini, F., Guyot, M. et al. Influence of Poly(DL-Lactide) Nanocapsules on the Biliary Clearance and Enterohepatic Circulation of Indomethacin in the Rabbit. Pharm Res 10, 750–756 (1993). https://doi.org/10.1023/A:1018924219540
Issue Date:
DOI: https://doi.org/10.1023/A:1018924219540