Microdose study of a P‐glycoprotein substrate,fexofenadine, using a non‐radioisotope‐labelled drug and LC/MS/MS

Objective: Fexofenadine is a P‐glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P‐glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic‐dose pharmacokinetics of fexofenadine from microdosing data using non‐radioisotope‐labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS). Method: In a single dose, randomized, two‐way crossover study, eight subjects received a microdose (100 μg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS. Results: Plasma concentration–time curves of fexofenadine between microdose and therapeutic dose were similar. The mean ± SD of C_max normalized to 60 mg dose after microdose and therapeutic dose were 379 ± 147 and 275 ± 145 ng/mL respectively. The mean AUC_last normalized to 60 mg dose after microdose and therapeutic dose were 1914 ± 738 and 1431 ± 432 ng/h/mL respectively. The mean dose‐adjusted C_max and AUC_last after microdose were higher compared with those after therapeutic dose. Individual plots of C_max and AUC_last normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova . Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose. Conclusion: For the P‐glycoprotein substrate fexofenadine, the predictability of therapeutic‐dose pharmacokinetics from microdose data was good. A microdose study using a non‐radioisotope‐labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.