Interaction of rocuronium with human liver cytochromes P450.
Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed.
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic. Electronic address: eva.anzenbacherova@upol.cz.
Eva
E
Anzenbacherova
Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Alena
A
Spicakova
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Lenka
L
Jourova
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Jitka
J
Ulrichova
Department of Anesthesiology and Resuscitation, Faculty Hospital, IP Pavlova 6, 775 15 Olomouc, Czech Republic.
Milan
M
Adamus
Department of Surgery II - Vascular and Transplantation Surgery, Faculty Hospital, IP Pavlova 6, 775 15 Olomouc, Czech Republic.
Petr
P
Bachleda
Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Pavel
P
Anzenbacher
D000732:Androstanols / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism / Q000502:physiology; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D000077123:Rocuronium
D000732:Androstanols; D065607:Cytochrome P-450 Enzyme Inhibitors; D003580:Cytochromes; D003473:Neuromuscular Nondepolarizing Agents; D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003975:Diazepam; D000077123:Rocuronium
Cytochrome P450; Drug interactions; Rocuronium