P. Platzer et al., Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver, INT J ONCOL, 19(6), 2001, pp. 1287-1293
10-Hydroxycamptothecin (HCPT), a natural analog of the alkaloid camptotheci
n (CPT), is a promising anticancer agent currently undergoing preclinical t
rials. Though HCPT is less toxic and more active in various human cancer ce
ll lines and in animal tumor models than the clinically approved CPT-analog
topotecan, little is known about its biotransformation products and their
route of elimination. To investigate the metabolism and biliary excretion,
livers of male Wistar rats were perfused with HCPT (5 muM). Bile and perfus
ate samples were collected for 60 min and quantified by reversed-phase high
-performance liquid chromatography (HPLC). Besides HCPT, three metabolites,
namely HCPT glucuronide (M1), hydroxyHCPT glucuronide (M2), and hydroxyHCP
T (M3) could be identified by enzymatic hydrolysis with beta -glucuronidase
and mass spectroscopy. Biliary secretion of HCPT and M1-M3 reached a peak
secretion of 1532 +/- 124, 75 +/- 16, 5.8 +/-1.6 and 2.1 +/-0.5 pmoles/g li
ver.min, respectively, after 25 min. The total amount of HCPT and M1-M3 exc
reted into bile during the time of perfusion (60 min) was low and represent
ed a mean of 9.9 +/-3.2%, 0.44 +/-0.17%, 0.041 +/-0.010%, and 0.022 +/-0.00
4% of the initial HCPT dose, respectively. In the perfusate, besides HCPT M
1 and M2 but not M3 could be detected (maximum concentrations after about 2
0 min: 3248 +/- 210, 16.8 +/-2.8 and 1.0 +/-0.4 pmoles/g liver.min, respect
ively). The cumulative efflux of HCPT and M1 and M2 into the perfusate was
21.1 +/-3.9%, 0.145 +/-0.036% and 0.018 +/-0.004% of the initial dose, resp
ectively, indicating a preferable non-biliary secretion for HCPT and a pred
ominant biliary elimination for conjugated HCPT biotransformation products.
In conclusion, HCPT is biotransformed in a rat liver model to three metabo
lites, mainly excreted into bile, which may be of clinical relevance during
cancer therapy.