3.4 Tissue distribution of ningetinib and M1 in mice.
In vitro experiments showed that M1 formation was less than 5%
in HLMs. In vivo experimental evidence that M1 in excreta
accounted for < 2% of the dose administered further supported
that N -demethylation was not the primary metabolic pathway of
ningetinib in humans. To provide a plausible explanation for high plasma
exposure of M1, the tissue distribution of ningetinib and M1 was
determined in mice because the metabolite profile of ningetinib in mice
was similar to that of the NSCLC patients (Table S2 and Figure S1).
According to Fig. 5A, after administering 10 mg·kg-1of ningetinib orally to the mice, the parent drug ningetinib exhibited
an extensive tissue distribution with a higher exposure in most tissues
than in plasma. Unlike the parent drug, the M1 concentrations in tissues
other than the liver were all lower than that in plasma (Fig. 5B).
Similar to human pharmacokinetics, the plasma concentration of M1 in
mice gradually increased over time and was even more than double the
parent drug. However, the M1 concentrations in tissues apart from the
liver were less than 30% of the parent drug (Fig. 5C). Plasma was the
preferred site for M1 disposition in vivo.