4β-hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans

We have proposed that 4 beta-hydroxycholesterol (4 beta-OHC) may be used as an endogenous marker of CYP3A activity. The cholesterol metabolite 4 beta-OHC is formed by CYP3A4. Treatment of patients with strong inducers of CYP3A enzymes, e.g. anti-epileptic drugs, resulted in 10-fold increased concentrations of plasma 4 beta-OHC, while treatment with CYP3A inhibitors such as ritonavir or itraconazole resulted in decreased plasma concentrations. There was a relationship between the 4 beta-OHC concentration and the number of active CYP3A5*1 alleles showing that 4 beta-OHC was not only formed by CYP3A4, but also by CYP3A5. The concentration of 4 beta-OHC was higher in women than in men, confirming previous studies indicating a gender difference in CYP3A4/5-activity. The rate of elimination of 4 beta-OHC is slow (half-life 17 days) which results in stable plasma concentrations within individuals, but limits its use to study rapid changes in CYP3A activity. In short-term studies exogenous markers such as midazolam or quinine may be superior, but in long-term studies 4 beta-OHC is a sensitive marker of CYP3A activity, especially to assess induction but also inhibition. Under conditions where the cholesterol concentration is changing, the ratio of 4 beta-OHC : cholesterol may be used as an alternative to 4 beta-OHC itself. The use of an endogenous CYP3A marker has obvious advantages and may be of value both during drug development and for monitoring CYP3A activity in patients.