1998 Annual Meeting Abstract Correction
Correction
The content of the abstract "A Soldner, LZ Benet, E Mutschler and U Christians.
Characterization of active transport of the AII-antagonist Losartan and its
metabolite EXP 3174 across MDCK-MDR1 and CACO-2 cells. AAPS PharmSci Supplement,
Volume 1, Number 1, #3800, November, 1998" was inadverdently switched during
publication in the AAPS PharmSci Supplement. The correct version has
been reinstalled in the electronic journal AAPS PharmSci and is displayed
below. We apologize for any inconvenience to the authors.
#3800
CHARACTERIZATION OF ACTIVE TRANSPORT OF THE AII-ANTAGONIST LOSARTAN AND ITS
METABOLITE EXP3174 ACROSS MDCK-MDR1 AND CACO-2 CELL MONOLAYERS. Andrea Soldner¹*,
Leslie Z. Benet¹, Ernst Mutschler²
and Uwe Christians¹. ¹Department
of Biopharmaceutical Sciences, School of Pharmacy, University of California,
San Francisco, CA 94143-0446. ²Department
of Pharmacology, J.W. Goethe-University, Biocenter Niederursel, 60439 Frankfurt/Main,
Germany.
Purpose. We studied the transport of the angiotensin-II antagonist
losartan and its active main metabolite EXP 3174 across monolayers of both P-glycoprotein-overexpressing,
stably MDR1-transfected Madin-Darby canine kidney cells (MDCK-MDR1) and human
Caco-2 cells. Methods. Epithelial layers of MDCK-MDR1 and Caco-2 cells,
grown to confluence on TranswellTM insert
membranes, were used to characterize the transcellular transport of losartan
and EXP 3174. Samples were directly analyzed by column-switch HPLC/UV-detection
with on-line solid-phase extraction. Results. Losartan was temperature-dependently
and saturably transported both in MDCK-MDR1 (KM, 403 ± 15 µM; VMAX,
200 ± 9 pmol·cm-2·min-1, PappA-B, 2.27·10-6
cm·s-1) and Caco-2 cells (KM, 232 ± 8 µM;
VMAX, 93 ± 3 pmol·cm-2·min-1,
PappA-B, 7.6·10-6 cm·s-1)
with a significantly greater basolateral-to-apical (B/A) flux compared to the
respective apical-to-basolateral (A/B) flux (ratio =31 in MDCK-MDR1 and ratio
3-5 in Caco-2 cells). The B/A flux of 40 µM losartan was completely blocked
in the presence of 10 µM cyclosporine and significantly inhibited in the presence
of 25 µM vinblastine (25% of control). In contrast, EXP 3174 was transported
in Caco-2 cells only (KM, 70 ± 3 µM; VMAX,
10 ± 1 pmol·cm-2·min-1,
PappA-B, 2.0·10-6
cm·s-1) displaying a B/A-to-A/B ratio of 5-6.
The B/A flux of 25 µM EXP 3174 was significantly inhibited by both 10 µM cyclosporine
and 25 µM vinblastine. Conclusions. Losartan, which is metabolized by
CYP3A4 and CYP2C9 to its main and active metabolite EXP 3174, is transported
by P-glycoprotein as well as one or more other intestinal drug transporters.
In comparison, its carboxylic acid metabolite EXP 3174 , which is not a P-glycoprotein
substrate, displays a considerably higher affinity for these other intestinal
drug transporters. This study provides further supporting evidence for the suggested
complementary role of CYP3A and P-glyco-protein in drug disposition and our
hypothesis that CYP3A metabolism creates metabolites which are better substrates
for the transporter(s) thereby enhancing drug excretion.
*Supported by the DFG, Germany (So 97/1-1)
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