title: Effects of calcium antagonists on binding of local anesthetics to plasma proteins and erythrocytes in mice.
abstract: This study was designed to document possible changes in the binding of bupivacaine (BV), lidocaine (LC) and their main metabolites desbutylbupivacaine (PPX) and monoethylglycinexylydide (MEGX), respectively, to plasma proteins and erythrocytes in mice after acute treatment with the calcium antagonists diltiazem (DZ), nicardipine (NP) and verapamil (VP). A significant plasma protein binding of BV, LC and PPX was measured, whereas no binding could be detected for MEGX. The binding of BV was not modified by DZ, NP and VP, however, the total plasma level was increased in the presence of VP. For PPX a significant increase in total and free plasma levels and a decrease in protein binding were demonstrated after DZ and VP treatment. Concerning LC, a significant increase in total and free plasma levels was documented for DZ, NP and VP suggesting an inhibition of the metabolism of LC by the calcium antagonists. An increased penetration of LC into erythrocytes was also demonstrated which is consistent with the calcium antagonist-induced increase in LC free plasma levels. These effects may contribute in part to the previously observed increase in toxicity of BV by calcium antagonists, but are not likely to be the sole mechanism.
authors.affiliation: Laboratoire de Pharmacologie médicale, Faculté de Médecine de Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Jacob
authors.forename: S
authors.initials: S
authors.lastname: Grignon
authors.forename: L
authors.initials: L
authors.lastname: Attolini
authors.forename: M
authors.initials: M
authors.lastname: Gantenbein
authors.forename: B
authors.initials: B
authors.lastname: Bruguerolle
mesh_terms: D000779:Anesthetics, Local / Q000097:blood*; D000818:Animals; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism*; D002045:Bupivacaine / Q000097:blood; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000097:blood; D008297:Male; D051379:Mice; D009529:Nicardipine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D001798:Blood Proteins; D002121:Calcium Channel Blockers; D008012:Lidocaine; D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem; D002045:Bupivacaine