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, 2ø,6ø-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 (mM, 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 mM and 250 mM, 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.

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“…Those studies were conducted in vitro, and it is worth noting that in vivo factors such as absorption, distribution, protein binding and metabolism in organs other than the liver have a clinical influence on ropivacaine metabolism. Furthermore, it is not known whether the propofol inhibitory effect on ropivacaine metabolism is seen clinically (10,11).…”