RIFAMPICIN INDUCTION OF LIDOCAINE METABOLISM IN CULTURED HUMAN HEPATOCYTES

In our laboratory, cultured human hepatocytes are being evaluated as a n experimental system to study drug interactions. We report the effect of a known cytochrome P450 (CYP) inducer, rifampicin, on the metaboli sm of lidocaine by primary human hepatocytes. Rifampicin has been show n to induce CYP3A4, a major human hepatic CYP isozyme that is known to metabolize lidocaine to its primary metabolite, monoethylglycinexylid ide. Human hepatocytes were cultured on collagen-coated plates in seru m-free, hormone-supplemented Waymouth medium for a 3-day period before they were treated with rifampicin at 50 mu M for 1 to 3 days. Hepatoc ytes isolated from five individuals were studied, and, in all cases, l idocaine metabolism was found to be induced by rifampicin, as demonstr ated by a higher rate of monoethylglycinexylidide formation than concu rrent controls. For three of the hepatocyte cultures, lidocaine metabo lism was evaluated-at various times after treatment. Induction was obs erved at 1 day after treatment, and reached higher levels at day 2 or 3. The level of induction was found to be approximately 100% for two h epatocyte isolations and approximately 600% for one isolation. In a se parate experiment, hepatocytes were treated with rifampicin for a 2-da y period. Rate of lidocaine metabolism at multiple substrate concentra tions (10-120 mu M) were then studied. Rifampicin induction of lidocai ne metabolism (approximately 100%) was observed at all the lidocaine c oncentrations studied. Lineweaver-Burk plot of the data showed an incr ease in V-max and a less significant change in K-m, Induction of lidoc aine metabolism by rifampicin (concentrations of 0.1-50 mu M) was foun d to be dose-dependent, with significant induction observed at 1 mu M and higher concentrations. Our results suggest that lidocaine metaboli sm in humans in vivo would be similarly affected by rifampicin. This m etabolic interaction observed between rifampicin and lidocaine should be considered for the adjustment of dose and dose-regiments if these d rugs were to be used in combination. Our results also suggest that CYP 3A4-inducing drugs such as rifampicin may complicate the proposed use of lidocaine metabolism as an index of hepatic function for patients w ith liver diseases.