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PIII‐2
Author(s) -
Kanaan M.,
Daali Y.,
Dayer P.,
Desmeules J.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.210
Subject(s) - metabolite , chemistry , p glycoprotein , tramadol , desmethyl , active metabolite , rhodamine 123 , pharmacology , caco 2 , enantiomer , in vitro , biochemistry , stereochemistry , biology , analgesic , multiple drug resistance , antibiotics
AIM We studied the involvement of P‐glycoprotein (P‐gP) in the transepithelial transport of the two enantiomers of tramadol (TMD) and that of its active metabolite O‐desmethyl‐tramadol (M1). METHODS We used the human intestinal Caco‐2 cell monolayer model. Transmission electron microscopy (TEM), transepithelial electrical resistance (TEER),[ 3 H]‐mannitol permeability, Western blot analysis and bidirectional transport of rhodamine 123 were performed to assess the integrity of the model. Bidirectional transport of 1, 10, 50 and 100μM of racemic TMD and M1 across the Caco‐2 monolayers was investigated in the presence and absence of the P‐gP inhibitor cyclosporine (10μM). TMD and M1 quantitation was performed using respectively a chiral and non‐chiral HPLC method. RESULTS We found that: i) (+)‐TMD, (−)‐TMD and M1 showed a statistically significant differential transport between the basolateral‐to‐apical (B‐A) and apical‐to‐basolateral (A‐B) direction (apparent permeability coefficient Papp(B‐A)/(A‐B): 2‐2.5); ii) A‐B transport was not affected by cyclosporine but B‐A transport was slightly increased in the presence of the inhibitor by 6 to 18% for TMD (+) and (−) and 14 to 26% for M1; iii) The transepithelial transport was concentration‐dependant. CONCLUSIONS The data indicate that TMD and its active metabolite M1 are not P‐gP substrates. However, it suggest that transporter(s) other than P‐gP might be involved in their intestinal transport. Moreover, TMD transport is not stereoselective. Clinical Pharmacology & Therapeutics (2005) 79 , P58–P58; doi: 10.1016/j.clpt.2005.12.210