Characterization of jejunal absorption and apical efflux of ropivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models

被引:66
作者
Berggren, S
Hoogstraate, J
Fagerholm, U
Lennernäs, H
机构
[1] Uppsala Univ, Div Pharmaceut, Dept Pharm, SE-75123 Uppsala, Sweden
[2] AstraZeneca R&D Sodertalje, Res DMPK, Sodertalje, Sweden
[3] AstraZeneca R&D Sodertalje, Expt Med, Sodertalje, Sweden
关键词
ropivacaine; bupivacaine; lidocaine; permeability; biopharmaceutical classification system; P-glycoprotein; rat; intestine; jejunum; Ussing chamber; intestinal perfusion; calcein AM assay; efflux; absorption predicition;
D O I
10.1016/j.ejps.2003.12.004
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The purpose of this study was to characterize the rat jejunal passive transport and the possible active efflux of three local anaesthetics, ropivacaine, lidocaine and bupivacaine using two different absorption models, the in situ single-pass intestinal perfusion and the in vitro Ussing chamber model, as well as P-glycoprotein (Pgp)-mediated calcein transport inhibition in Caco-2 cells. Concentration and pH dependence, efflux inhibition by verapamil and digoxin and bi-directional permeability studies were performed to investigate the potential involvement of efflux carriers in the intestinal absorption of the local anaesthetics. In the jejunal perfusion the permeability of these agents appeared to be high, predicting complete intestinal absorption (>90%). There was no effect of the Pgp inhibitors on net absorption for any of the local anaesthetics in the two absorption models. However, in the Ussing chamber at an equal pH of 7.4 at mucosal and serosal sides, the observed jejunal permeability ratios (S-M)/(M-S), of 2.3, 1.8 and 3.0 for ropivacaine, lidocaine and bupivacaine, respectively, indicated at least some involvement of carrier-mediated intestinal secretion. This idea was supported in the calcein AM Pgp transport assay in which two of the tested local anaesthetic agents affected cellular calcein retention. As anticipated for these agents, the mucosal pH conditions were shown to largely affect the gut permeability. The jejunal permeabilifes of the local anaesthetics as measured in the two absorption models fitted well in a model comparison that incorporated the permeabilities of six other structurally unrelated drugs. In conclusion, the jejunal permeability of ropivacaine, lidocaine and bupivacaine was high and although evidence was obtained for carrier-mediated intestinal efflux this process appeared not to have a significant influence on the rate and extent of in vivo intestinal absorption. Rather, passive diffusion of these agents seems to be the major mechanism for the intestinal absorption. (C) 2004 Elsevier B.V. All rights reserved.
引用
收藏
页码:553 / 560
页数:8
相关论文
共 42 条
[1]   CHANGES IN INTRACELLULAR OR EXTRACELLULAR PH DO NOT MEDIATE P-GLYCOPROTEIN-DEPENDENT MULTIDRUG-RESISTANCE [J].
ALTENBERG, GA ;
YOUNG, G ;
HORTON, JK ;
GLASS, D ;
BELLI, JA ;
REUSS, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (20) :9735-9738
[2]   A THEORETICAL BASIS FOR A BIOPHARMACEUTIC DRUG CLASSIFICATION - THE CORRELATION OF IN-VITRO DRUG PRODUCT DISSOLUTION AND IN-VIVO BIOAVAILABILITY [J].
AMIDON, GL ;
LENNERNAS, H ;
SHAH, VP ;
CRISON, JR .
PHARMACEUTICAL RESEARCH, 1995, 12 (03) :413-420
[3]  
Arlander E, 1996, ALIMENT PHARM THERAP, V10, P73
[4]   Mammalian ABC transporters in health and disease [J].
Borst, P ;
Elferink, RO .
ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :537-592
[5]   Tissue distribution and chemical induction of multiple drug resistance genes in rats [J].
Brady, JM ;
Cherrington, NJ ;
Hartley, DP ;
Buist, SC ;
Li, N ;
Klaassen, CD .
DRUG METABOLISM AND DISPOSITION, 2002, 30 (07) :838-844
[6]  
Chiou WL, 2001, INT J CLIN PHARM TH, V39, P93
[7]   Evaluation of a vincristine resistant Caco-2 cell line for use in a calcein AM extrusion screening assay for P-glycoprotein interaction [J].
Eneroth, A ;
Åström, E ;
Hoogstraate, J ;
Schrenk, D ;
Conrad, S ;
Kauffmann, HM ;
Gjellan, K .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2001, 12 (03) :205-214
[8]  
Fagerholm U, 1999, ACTA PHYSIOL SCAND, V165, P315
[9]   Comparison between permeability coefficients in rat and human jejunum [J].
Fagerholm, U ;
Johansson, M ;
Lennernas, H .
PHARMACEUTICAL RESEARCH, 1996, 13 (09) :1336-1342
[10]   High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy [J].
Farrell, RJ ;
Murphy, A ;
Long, A ;
Donnelly, S ;
Cherikuri, A ;
O'Toole, D ;
Mahmud, N ;
Keeling, PWN ;
Weir, DG ;
Kelleher, D .
GASTROENTEROLOGY, 2000, 118 (02) :279-288