rifampin and monoethylglycinexylidide

The N-deethylation of lignocaine to monoethylglycinexylidide (MEGX) is partially catalysed by the rifampicin inducible P-450 isoenzyme CYP3A4. This has led to the use of the MEGX test (MEGX plasma concentrations after i.v. lignocaine) as a marker of CYP3A4 activity. To test this hypothesis, we studied lignocaine and MEGX plasma pharmacokinetics.. Ten healthy volunteers received rifampicin (600 mg day(-1)) for 6 days, resulting in a four- to sixfold increase in urinary 6beta-hydroxycortisol output. On days 1 and 7 (pretreatment), day 11 (treatment), and day 14 (48 h after rifampicin), 50 mg lignocaine i.v. was administered. MEGX concentrations at 30 min [MEGX30min] were assessed and normalised to MEGX test results after 1 mg kg(-1) lignocaine. On days 7 and 14 the lignocaine and MEGX plasma concentrations were measured over a 300 min period. MEGX test results and lignocaine and MEGX plasma pharmacokinetics before and after induction with rifampicin were compared.. The lignocaine plasma clearance increased from 7.5+/-1.2 ml min(-1) kg(-1) before to 8.6+/-2ml min(-1) kg(-1) (P=0.026) after induction. The normalised MEGX30min concentrations increased from 61+/-14 (day 7) to 82+/-34 microg l(-1) (day 14) by a mean of 21 microg l(-1) (95% confidence interval: -3 to 44 microg l(-1)) (P=0.055).. An insignificant increase of MEGX plasma concentrations was found in 10 volunteers after induction of CYP3A4 activity by rifampicin. Therefore, the MEGX test is not a sensitive marker of P-450 induction in healthy human liver.

Topics: Adult; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Lidocaine; Liver Function Tests; Male; Mixed Function Oxygenases; Reproducibility of Results; Rifampin

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)

Topics: Aged; Cells, Cultured; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Humans; Lidocaine; Liver; Male; Middle Aged; Rifampin