EVALUATION OF MICRODOSING TO ASSESS PHARMACOKINETIC LINEARITY IN RATS USING LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY
Drug Metabolism and Disposition December 3, 2005 Suresh K. Balani, N. Nagaraja, Mark G. Qian et al. 61 citations
Conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) can characterize pharmacokinetics of nonlabeled drugs at a microdose of 1 microg/kg in rats, offering a more accessible alternative to accelerator mass spectrometry (AMS) for microdosing studies. For fluconazole and tolbutamide, exposure was linear between the microdose and doses 1000-fold higher, supporting LC-MS/MS's utility in human microdosing. However, for an investigational compound MLNX, pharmacokinetics in rats were nonlinear, suggesting its microdose pharmacokinetics in humans might not reflect therapeutic doses. These findings indicate LC-MS/MS is adequate for microdose pharmacokinetic assessment in humans, though nonlinearity in some compounds may limit predictability.