Abstract

In our laboratory, cultured human hepatocytes are being evaluated as an experimental system to study drug interactions. We report the effect of a known cytochrome P450 (CYP) inducer, rifampicin, on the metabolism of lidocaine by primary human hepatocytes. Rifampicin has been shown to induce CYP3A4, a major human hepatic CYP isozyme that is known to metabolize lidocaine to its primary metabolite, monoethylglycinexylidide. Human hepatocytes were cultured on collagen-coated plates in serum-free, hormone-supplemented Waymouth medium for a 3-day period before they were treated with rifampicin at 50 microM for 1 to 3 days. Hepatocytes isolated from five individuals were studied, and, in all cases, lidocaine metabolism was found to be induced by rifampicin, as demonstrated by a higher rate of monoethylglycinexylidide formation than concurrent controls. For three of the hepatocyte cultures, lidocaine metabolism was evaluated at various times after treatment. Induction was observed 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 hepatocyte isolations and approximately 600% for one isolation. In a separate experiment, hepatocytes were treated with rifampicin for a 2-day period. Rate of lidocaine metabolism at multiple substrate concentrations (10-120 microM) were then studied. Rifampicin induction of lidocaine metabolism (approximately 100%) was observed at all the lidocaine concentrations studied. Lineweaver-Burk plot of the data showed an increase in Vmax and a less significant change in Km. Induction of lidocaine metabolism by rifampicin (concentrations of 0.1-50 microM) was found to be dose-dependent, with significant induction observed at 1 microM and higher concentrations. (ABSTRACT TRUNCATED AT 250 WORDS)