title: Effects of premedication medicines on the formation of the CYP3A4-dependent metabolite of ropivacaine, 2', 6'-Pipecoloxylidide, on human liver microsomes in vitro.
abstract: Ropivacaine is a relatively new amide-type local anaesthetic, mainly used for surgery and postoperative pain relief. In this study we have investigated the interaction between the CYP3A4 metabolite of ropivacaine, 2',6'-pipecoloxylidide (PPX), and premedication with, i.e., psychotropic and antianxiety agents (diazepam, midazolam), hypnotics (thiamylal), local anaesthetics (lidocaine), depolarizing muscular relaxants (vecuronium), antihypertensive (clonidine) and H(2)-receptor antagonist (cimetidine) using human liver microsomes in vitro. The effects of the interaction between PPX and premedications were examined using a human liver microsomal preparation in vitro. The concentrations of ropivacaine and PPX were determined by HPLC with UV detection. The apparent Michaelis-Menten constant (Km) and the maximal velocity of total metabolic formation (V(max)) of PPX, the main metabolite of ropivacaine in human liver microsomes, were 17.7 (microM, mean) and 711 (nmol/min./mg protein, mean), respectively. Five premedications (diazepam, lidocaine, cimetidine, vecuronium and clonidine) did not inhibit ropivacaine metabolism in human liver microsomes at concentrations within the therapeutic range. However, midazolam and thiamylal weakly inhibited ropivacaine metabolism in competitive manner (IC(50) 7.8 microM and 250 microM, respectively). The results show lack of interaction between ropivacaine and seven premedication medicines within the therapeutic range of ropivacaine using human liver microsomes in vitro.
authors.affiliation: Institute of Community Medicine, University of Tsukuba, Ibaraki-ken 305-8575, Japan. einosuke@md.tsukuba.ac.jp
authors.forename: Einosuke
authors.initials: E
authors.lastname: Tanaka
authors.forename: Takako
authors.initials: T
authors.lastname: Nakamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inomata
authors.forename: Katsuya
authors.initials: K
authors.lastname: Honda
mesh_terms: D000577:Amides / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000494:pharmacology; D011292:Premedication; D000077212:Ropivacaine; D013840:Thiamylal / Q000494:pharmacology; D014673:Vecuronium Bromide / Q000494:pharmacology
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D013840:Thiamylal; D014673:Vecuronium Bromide; D000077212:Ropivacaine; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003000:Clonidine; C025149:2',6'-pipecoloxylidide; D003975:Diazepam; D008874:Midazolam; D002045:Bupivacaine