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Titolo:
Effect of chronic bile duct obstruction and LPS upon targeting of naproxento the liver using naproxen-albumin conjugate
Autore:
Albrecht, C; Melgert, BN; Reichen, J; Poelstra, K; Meijer, DKF;
Indirizzi:
Univ Bern, Dept Clin Pharmacol, Bern, Switzerland Univ Bern Bern Switzerland Bern, Dept Clin Pharmacol, Bern, Switzerland GUIDE, Dept Pharmacokinet & Drug Delivery, Groningen, Netherlands GUIDE Groningen Netherlands net & Drug Delivery, Groningen, Netherlands
Titolo Testata:
JOURNAL OF DRUG TARGETING
fascicolo: 2, volume: 6, anno: 1998,
pagine: 105 - 117
SICI:
1061-186X(1998)6:2<105:EOCBDO>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN SERUM-ALBUMIN; HYPERDYNAMIC CIRCULATION; BILIARY-CIRRHOSIS; ENDOTOXIC-SHOCK; RAT-LIVER; PHARMACOKINETICS; METABOLISM; CELLS; NECROSIS; DISEASE;
Keywords:
biliary cirrhosis; liver targeting; LPS; naproxen; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Meijer, DKF Univ Ctr Pharm, Deusinglaan 1, NL-9713 AV Groningen, Netherlands Univ Ctr Pharm Deusinglaan 1 Groningen Netherlands NL-9713 AV
Citazione:
C. Albrecht et al., "Effect of chronic bile duct obstruction and LPS upon targeting of naproxento the liver using naproxen-albumin conjugate", J DRUG TAR, 6(2), 1998, pp. 105-117

Abstract

Naproxen covalently linked to human serum albumin (NAP-HSA) is efficientlytargeted to endothelial and Kupffer cells of the liver and may offer a newtherapeutic approach in the treatment of liver disease associated with inflammatory processes. In the present investigation we explored the pharmacokinetic behaviour of targeted and non-targeted naproxen as well as the pharmacokinetic properties of the active metabolite, Naproxen-lysine (Nap-lysine), in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthermore, we studied the effect of endotoxemia, experimentally induced by intravenous injection of 800 mu g/kg lipopolysaccaride (LPS) upon the pharmacokinetics of these agents in order to investigate the feasibility of targeting naproxen to nonparenchymal cells in the inflamed and fibrotic liver. Ourstudies demonstrate that liver disease altered the pharmacokinetic behaviour of the different naproxen compounds. Thus, initial plasma concentrationsof NAP-HSA and naproxen were markedly lower in BDL rats accompanied by an increase of the volume of distribution during the terminal elimination phase(Vd(beta) BDL vs control 114 +/- 63 vs 50 +/- 7 and 202 +/- 24 vs 115 +/- 11 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas the naproxen treated control animals showed an increase in the terminal volume of distribution (176 +/- 34 vs 115 +/- 11 ml/kg) as well as an elevationof the plasma half-life (171 +/- 27 vs 116 +/- 14 min). The feasibility oftargeting naproxen to the chronically diseased liver could be clearly demonstrated: 15 min after administration of the conjugate 46% and 55% of the administered dose was found in the liver of CTR and BDL rats, whereas after injection of free naproxen only 5% and 12% of the dose was detected in liver tissue, respectively. We conclude that targeting albumin-linked naproxen to non-parenchymal cells in the liver is still feasible under the pathological conditions induced in the present study. Liver fibrosis induced significant alterations in thepharmacokinetic behaviour of the studied compounds.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/09/20 alle ore 12:18:52