Plasma 6ß-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 6ß-hydroxycortisol to cortisol concentration (6ß-OHF/F) ratio as a minimally invasive CYP3A phenotyping method. METHODS: Plasma 6ß-OHF and cortisol concentrations were measured via liquid chromatography/tandem mass spectrometry. The plasma 6ß-OHF/F ratio was compared with 6ß-hydroxylation clearance of endogenous cortisol (CLm(6ß); which we previously developed as an index of CYP3A activity) before, during and after oral contraceptive administration in 3 healthy women. The plasma 6ß-OHF/F ratio was observed during oral clarithromycin administration. The plasma 6ß-OHF/F ratio was also measured in 39 healthy participants. RESULTS: The plasma 6ß-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 CLm(6ß) values (43, 54 and 59%, respectively). Plasma 6ß-OHF/F ratio and CLm(6ß) exhibited a good correlation (r = .9053). The 6ß-OHF/F ratio decreased from 0.00921 to 0.00577 only 3 h following clarithromycin administration. The plasma 6ß-OHF/F ratio ranged 0.00565-0.01556 in 39 healthy participants. CONCLUSION: Based on its close relationship with CLm(6ß) and its decrease upon inhibition by clarithromycin, the plasma 6ß-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.

Quantification of fluticasone propionate in human plasma by LC-MS/MS and its application in the pharmacokinetic study of nasal spray at clinical doses.

We developed a method for quantifying fluticasone propionate (FP) using general-purpose liquid chromatography-tandem mass spectrometry equipment to measure the plasma concentration of FP for the pharmacokinetic study of FP following the administration of a prescribed nasal spray dose (100 µg). Using ammonium acetate (0.01 M)-formic acid (pH 2.9; 499:1, v/v) and methanol as the mobile phase, 3 pg/mL of FP was quantified. The relative error and standard deviation of the lower limit of quantification were <3.1%. The intra- and interday assay reproducibility was <3.5%. After 15 min of administering 200 µg FP nasal spray as the first dose, the FP concentration detected in the plasma of the two participants was 3.99 and 3.69 pg/mL. Subsequent doses of 100 µg FP were administered twice daily. The area under the plasma concentration-time curve values after 8-10 days of repeated administration of 100 µg of FP were approximately 1.6-fold higher than those achieved following a single administration of 200 µg of FP, which confirmed drug accumulation. The bioavailability of nasal FP was estimated to be 2% and 4%. This knowledge might help in reducing anxiety among patients who avoid using FP nasal spray, fearing its adverse effects.