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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot We have suggested that 4 beta-hydroxycholesterol may be used as an endogenous marker of CYP3A activity. center dot Recently, we found unexpectedly that the plasma concentration of 4 beta-hydroxycholesterol continued to increase for several weeks after complete induction of CYP3A4/5 by carbamazepine. center dot In the present study we investigated the time course of elimination of 4 beta-hydroxycholesterol from the circulation following CYP3A induction with rifampicin. WHAT THIS STUDY ADDS center dot 4 beta-Hydroxycholesterol is eliminated very slowly from the circulation with an apparent half-life of 17 days. center dot The long half-life results in a low variation in plasma concentration with time, but excludes 4 beta-hydroxycholesterol as a marker for rapid changes in CYP3A activity. The oxysterol 4 beta-hydroxycholesterol has been suggested as a marker for CYP3A4/5 activity. We have previously shown that plasma 4 beta-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 4 beta-hydroxycholesterol after termination of induction of CYP3A4/5 by rifampicin. An additional aim was to determine the variation in plasma level of 4 beta-hydroxycholesterol with time in 12 untreated healthy volunteers. 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 4 beta-hydroxycholesterol concentrations. Plasma levels of 4 beta-hydroxycholesterol were determined by isotope-dilution gas chromatography-mass spectrometry. Rifampicin treatment increased plasma 4 beta-hydroxycholesterol levels. After termination of rifampicin treatment plasma levels of 4 beta-hydroxycholesterol decreased slowly with an apparent half-life of 17 days. The intraindividual variation in plasma levels of 4 beta-hydroxycholesterol in untreated subjects was low, with coefficients of variation of between 4.8 and 13.2% over a period of 3 months. After termination of induction of CYP3A4/5, plasma 4 beta-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.