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Titolo:
PHARMACOKINETICS AND PHARMACODYNAMICS OF THE LEUKOTRIENE B-4 RECEPTORANTAGONIST CP-105,696 IN MAN FOLLOWING SINGLE ORAL-ADMINISTRATION
Autore:
LISTON TE; CONKLYN MJ; HOUSER J; WILNER KD; JOHNSON A; APSELOFF G; WHITACRE C; SHOWELL HJ;
Indirizzi:
PFIZER INC,DEPT DRUG METAB,DIV CENT RES,EASTERN POINT RD GROTON CT 06340 PFIZER INC,DEPT CLIN RES & CANC,DIV CENT RES GROTON CT 06340 PFIZER INC,DIV CENT RES,DEPT IMMUNOL & INFECT DIS GROTON CT 06340 OHIO STATE UNIV,COLL MED,DEPT PHARMACOL COLUMBUS OH 43210
Titolo Testata:
British journal of clinical pharmacology
fascicolo: 2, volume: 45, anno: 1998,
pagine: 115 - 121
SICI:
0306-5251(1998)45:2<115:PAPOTL>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
COLLAGEN-INDUCED ARTHRITIS; CLINICAL PHARMACOKINETICS; CHEMOTACTIC FACTORS; 5-LIPOXYGENASE; PSORIASIS; ADHESION; LY255283; SC-41930; INVIVO; MAC-1;
Keywords:
LEUKOTRIENE B-4; RECEPTOR ANTAGONIST; CD11B; NEUTROPHIL; PHARMACOKINETICS; PHARMACODYNAMICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
T.E. Liston et al., "PHARMACOKINETICS AND PHARMACODYNAMICS OF THE LEUKOTRIENE B-4 RECEPTORANTAGONIST CP-105,696 IN MAN FOLLOWING SINGLE ORAL-ADMINISTRATION", British journal of clinical pharmacology, 45(2), 1998, pp. 115-121

Abstract

Arms CP-105,696, 3S,4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP-105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg.Methods Forty-eight subjects participated in a randomized, double-blind, parallel group study. Plasma and urine concentrations of CP-105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP-105,696, the inhibiton of LTB4-inducedupregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration usingan ex vivo whole blood flow cytometry assay. Results C-max and AUC(0,infinity) increased in a dose-related manner. Respective mean C-max values were 0.54 to 30.41 mu g ml(-1) following doses of 5 to 640 mg. Respective mean AUC(0,infinity) values were 1337 to 16819 mu g ml(-1) h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half-lives ranging from 289 to 495 h. Group mean terminal elimination half-lives were dose-independent. Urinary excretion of unchanged drug accounted for <1% ofthe administered dose. A linear relationship was observed between CP-105,696 plasma concentrations and inhibition of LTB4-mediated CD11b upregulation on human neutrophils in whole blood. CP-105,696 plasma concentrations of 5-6 mu g ml(-1) were necessary to elicit a two-fold shift to the right of the LTB4 concentration response curve for CD11b upregulation. Conclusions These studies demonstrate pharmacologically significant LTB4-receptor antagonism following a single dose of CP-105,696and pharmacokinetics consistent with once-daily dosing.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/01/21 alle ore 03:53:32