3.3. Pharmacokinetic studies
With oral administration of 10 mg/kg RA and A1 to 12 individual
Sprague–Dawley rats, this method was validated and proven to be
suitable for use in PK studies. The concentration-time data of A1 and RA
corresponded to the two-compartment pharmacokinetic model. Fig. 5 shows
the mean plasma concentration-time curve (mean ± SD) of RA and A1 after
administration of a dose. In spite of dosage differences, these RA
values did not differ significantly from those reported by Yang et
al.[13] and Noguchi-Shinohara et al.[14]. By replacing the O
atom with an N atom, no significant difference was observed between the
times to reach the maximum A1 and RA plasma concentrations; however,
Cmax increased from 209.3 ± 9.4 to 255.0 ± 20.8 min, and
the area under the plasma concentration-time curve from 0 min to the
time of the last measurable concentration (AUC0–t) was
twice that of RA, 16,859.2 ± 1,174.1 ng/ml min, amounting to 36,677.5 ±
4,493.6 ng/ml min. At the terminal phase, the drug elimination half-life
(t1/2) also increased from 108.4 ± 13.1 to 366.3 ± 12.2
min.
Obviously,
from the results, A1 has a higher oral bioavailability than RA, which
may indicate a direction for the structural modification of such
substances. The mechanisms of A1 need to be clarified by additional
studies.