WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • We have suggested that 4β‐hydroxycholesterol may be used as an endogenous marker of CYP3A activity.• Recently, we found unexpectedly that the plasma concentration of 4β‐hydroxycholesterol continued to increase for several weeks after complete induction of CYP3A4/5 by carbamazepine.• In the present study we investigated the time course of elimination of 4β‐hydroxycholesterol from the circulation following CYP3A induction with rifampicin. WHAT THIS STUDY ADDS • 4β‐Hydroxycholesterol is eliminated very slowly from the circulation with an apparent half‐life of 17 days.• The long half‐life results in a low variation in plasma concentration with time, but excludes 4β‐hydroxycholesterol as a marker for rapid changes in CYP3A activity.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.

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