4β-Hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin

Abstract

AIMS: The oxysterol 4β-hydroxycholesterol has been suggested as a marker for CYP3A4/5 activity. We have previously shown that plasma 4β-hydroxycholesterol continues to increase for several weeks after maximal induction of CYP3A4/5 by carbamazepine at the dose given. In the present study we aimed to determine the time course of the decrease in plasma 4β-hydroxycholesterol after termination of induction of CYP3A4/5 by rifampicin. An additional aim was to determine the variation in plasma level of 4β-hydroxycholesterol with time in 12 untreated healthy volunteers. METHODS: Twenty-four healthy subjects were allocated into three study groups of equal sizes. The volunteers were treated with rifampicin (either 20 mg day -1, 100 mg day-1 or 500 mg day-1) for 2 weeks. Blood samples were taken before, during and after rifampicin treatment. In another group of 12 untreated volunteers blood samples were collected at different time points in order to determine the intraindividual variations in plasma 4β-hydroxycholesterol concentrations. Plasma levels of 4β-hydroxycholesterol were determined by isotope-dilution gas chromatography-mass spectrometry. RESULTS: Rifampicin treatment increased plasma 4β-hydroxycholesterol levels. After termination of rifampicin treatment plasma levels of 4β-hydroxycholesterol decreased slowly with an apparent half-life of 17 days. The intraindividual variation in plasma levels of 4β-hydroxycholesterol in untreated subjects was low, with coefficients of variation of between 4.8 and 13.2% over a period of 3 months. CONCLUSIONS: After termination of induction of CYP3A4/5, plasma 4β-hydroxycholesterol levels decreased slowly during 8 weeks. The half-life of elimination (17 days) resembled that of cholesterol rather than other oxysterols. The long half-life results in stable plasma concentrations with time. © 2008 The Authors.