Plasma 6β-hydroxycortisol to cortisol ratio as a less invasive cytochrome P450 3A phenotyping method.

Aim: A less invasive evaluation method of cytochrome P450 3A (CYP3A) activity provides an important tool for personalized medicine. We aimed to clarify the usefulness of the plasma 6β-hydroxycortisol to cortisol concentration (6β-OHF/F) ratio as a minimally invasive CYP3A phenotyping method.

Methods: Plasma 6β-OHF and cortisol concentrations were measured via liquid chromatography/tandem mass spectrometry. The plasma 6β-OHF/F ratio was compared with 6β-hydroxylation clearance of endogenous cortisol (CL; which we previously developed as an index of CYP3A activity) before, during and after oral contraceptive administration in 3 healthy women. The plasma 6β-OHF/F ratio was observed during oral clarithromycin administration. The plasma 6β-OHF/F ratio was also measured in 39 healthy participants.

Results: The plasma 6β-OHF/F ratio in 3 healthy women on Day 21 of starting oral contraceptive administration decreased by 39, 49 and 61% compared with Day 0. These values were similar to CL values (43, 54 and 59%, respectively). Plasma 6β-OHF/F ratio and CL exhibited a good correlation (r = .9053). The 6β-OHF/F ratio decreased from 0.00921 to 0.00577 only 3 h following clarithromycin administration. The plasma 6β-OHF/F ratio ranged 0.00565-0.01556 in 39 healthy participants.

Conclusion: Based on its close relationship with CL and its decrease upon inhibition by clarithromycin, the plasma 6β-OHF/F ratio serves as an index of CYP3A activity. Using this minimally invasive index, we can identify patients with extremely low CYP3A activity before treatment initiation and optimize the initial drug dose, thereby mitigating the risk of severe adverse reactions.